KR20230170032A - Phosphorus derivatives as novel SOS1 inhibitors - Google Patents

Abstract

(여기서 R¹, R², R³, R⁴, R⁵, R⁶, X₁, X₂, X₃, X₄ 및 Y는 본원에 정의된 바와 같음), 상기 화합물의 제조 방법, 상기 화합물을 제조하는 데 유용한 중간체 화합물, 상기 화합물을 포함하는 제약 조성물 및 조합물, 및 단독 작용제로서 또는 다른 활성 성분과 조합하여 질환, 특히 과다증식성 장애, 특히 SOS1과 연관된 질환의 치료 또는 예방을 위한 제약 조성물을 제조하기 위한 상기 화합물의 용도를 포함한다.The present invention relates to phosphorus derivatives of the formula (I):

(wherein R ¹ _, R ² , _R ³ , R ⁴ , R ⁵ , R ⁶ , X ₁ , X ₂ , Intermediate compounds useful for preparing, pharmaceutical compositions and combinations comprising said compounds, and pharmaceutical compositions for the treatment or prevention of diseases, especially hyperproliferative disorders, especially diseases associated with SOS1, as single agents or in combination with other active ingredients. Includes the use of the above compounds to prepare.

Description

Phosphorus derivatives as novel SOS1 inhibitors

The present invention relates to novel SOS1 inhibitors of formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful in preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and diseases. , in particular the use of said compounds as single agents or in combination with other active ingredients for preparing pharmaceutical compositions for the treatment or prevention of hyperproliferative disorders, in particular diseases associated with SOS1.

The present invention includes phosphorus derivatives of formula (I) that inhibit Ras-Sos1 interaction:

.

.

US 2011/0054173 A1 is selected from certain 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridine and 1- or 2-(4-(heteroaryloxy)- Phenyl)ethylamino-, oxy- or sulfanyl)pteridine and its use as pesticides and animal health products are disclosed.

2-position substituted quinazoline compounds are described for example in EP 0326328, EP 0326329, WO93/007124, WO2003/087098 and US 5,236,925. These compounds are not described as pharmaceutically active compounds, or, if they are described as pharmacologically active compounds, they are described as compounds having affinity for the epidermal growth factor receptor (EGFR).

Skin toxicity in the majority (45-100%) of patients receiving EGFR inhibitors is a class-specific side effect that typically presents as a papulopustular rash. Skin toxicity is associated with inhibition of EGFR in the skin, which is crucial in the normal development and physiology of the epidermis.

However, the state of the art does not describe:

A phosphorus derivative of formula (I) of the invention as described and defined herein, which is a derivative that possesses a phosphorus-containing functional group and effectively and selectively inhibits the Ras-Sos1 interaction.

Ras protein plays an important role in human cancer. Mutations in the Ras protein can be found in 20-30% of all human tumors and are recognized as drivers of tumorigenesis, especially in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer). Three types of human Ras encode four different Ras proteins of 21 kDa in size: H-Ras, N-Ras, and two splice variants of K-Ras, namely K-Ras 4A and K-Ras-4B. The genes are known. All Ras isoforms are highly conserved within the GTP-binding domain and differ primarily in the hypervariable C-terminal region. The C-termini of the different Ras-isoforms are post-translationally modified by lipidation (farnesylation, palmitoylation) to facilitate membrane anchorage. Localization of Ras-proteins at the cytoplasmic membrane provides proximity to transmembrane growth receptors and has been shown to be essential for transduction of growth signals from extracellular growth factor binding to intracellular downstream pathways. A variety of upstream signals can activate Ras proteins depending on the cellular context, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), nerve growth factor receptor (NGFR), etc. Activated Ras can signal through various downstream pathways, such as the Raf-MEK-ERK or PI3K-PDK1-Akt pathways.

At the molecular level, Ras proteins function as molecular switches. By binding to GTP and GDP, they exist in active (GTP-bound) and inactive (GDP-bound) states within the cell. Active GTP-loaded Ras recruits other proteins by binding of its cognate Ras-binding domain (RBD), resulting in activation of effector proteins followed by downstream signaling events, such as cytoskeletal rearrangements or transcriptional activation. cause. The activity state of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEF functions as an activator of Ras by promoting nucleotide exchange from GDP to GTP. GAP inactivates Ras-GTP by catalyzing the hydrolysis of bound GTP to GDP. In cancer cells, point mutations within the GTP-binding region, typically at codon 12, eliminate the ability of RAS to efficiently hydrolyze bound GTP, even in the presence of GAP. Therefore, cancer cells contain increased levels of active mutated Ras-GTP, which is believed to be a key factor for inducing cancer cell proliferation.

To date, three major families of RAS-specific GEFs have been identified (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al. 2011, Genes & Cancer 2(3) 298-305). Two son of sevenless (SOS) proteins (SOS1 and SOS2), four different isoforms of Ras guanine nucleotide release protein (Ras-GRP1-4) and two Ras guanine nucleotide release factors ( Ras-GRF1 and 2) are present. SOS proteins are ubiquitously expressed and are recruited to sites of activated growth factors. Ras-GRFs are predominantly expressed in the nervous system, where they are involved in calcium-dependent activation of Ras. In contrast, Ras GRP proteins are expressed in hematopoietic cells and act cooperatively with non-receptor tyrosine kinases. In relation to cancer, it has been found that SOS proteins are mainly involved.

Targeting Ras for cancer therapy has been the realm of dreams since the 1990s (Downward 2002 Nature Reviews Cancer, Krens et al. 2010 Drug Discovery Today). Due to its compact nature and high affinity for GDP and GTP combined with high intracellular GTP concentration, the Ras protein itself has always been considered undruggable, which means an opportunity to identify small chemical molecules that can bind to and inhibit active Ras. was evaluated as extremely low. Alternative approaches have been undertaken to reduce Ras signaling, for example using more promising drug targets, such as enzymes involved in post-translational modifications of Ras proteins, particularly farnesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer). Inhibitors (FTIs) of farnesyltransferase have been identified and developed to have promising antitumor effects in preclinical models. Unexpectedly, in clinical trials these inhibitors had limited efficacy. Targeting of upstream and downstream kinases involved in the Ras signaling pathway was more successful. Several drugs are in clinical trials for inhibiting different kinases, such as EGFR, Raf, MEK, Akt, PI3K (Takashima & Faller 2013 Expert Opin. Ther. Targets). Commercially available cancer drugs that inhibit Raf, EGFR or MEK are available.

Nonetheless, there still remains a large unmet need for the treatment of Ras-dependent tumors that are resistant to current therapies. Many research groups are in the process of identifying small molecules that directly target Ras (Ras small molecules have been described in the literature [Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al. 2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin-Ramos et al. (reviewed in Seminars in Cancer Biology). One group of inhibitors includes small molecules that inhibit the interaction of Ras with its effectors Raf or PI3K. Another group of compounds acts as covalent inhibitors of a specific cysteine mutant form of K-Ras (glycine to cysteine point mutation G12C). Because wild-type Ras protein should not be affected, specific targeting of the Ras-G12C mutant may have the advantage of reduced side effects. Additionally, several reports show small molecules and peptides that interfere with GEF co-activation of Ras (Hillig et al. 2019 PNAS; Gray et al. 2019 Angewandte Chemie). Several different binding sites leading to this mode of action are believed to be possible. Inhibitors can bind Ras or GEF in an allosteric or orthosteric manner. All these approaches of direct Ras-targeting are in the preclinical research phase. The stabilized peptide was shown to be active in the nanomolar range. (Leshchiner et al. 2015 PNAS). Its usefulness as a drug in clinical settings awaits.

The epidermal growth factor receptor (EGFR) is activated upon binding to epidermal growth factor and other growth factor ligands, triggering several downstream pathways including RAS/MAPK, PI3K/Akt, and STAT, which regulate different cellular processes including DNA synthesis and proliferation. It is a tyrosine kinase (TK) receptor (Russo A, Oncotarget.4254, 2015). The family of HER (ErbB) receptor tyrosine kinases consists of four members: the epidermal growth factor receptors [EGFR (HER1 or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4)]. Overexpression, mutation, or abnormal activity of these receptors has been implicated in various types of cancer (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147).

first generation inhibitors

Erlotinib and gefitinib are small molecule inhibitors of the EGFR/HER-1 (human epidermal growth factor receptor) tyrosine kinase. Erlotinib and gefitinib are reversible, highly specific small molecule tyrosine kinase inhibitors that inhibit autophosphorylation and block downstream signaling by competitively blocking the binding of adenosine triphosphate to its binding site within the tyrosine kinase domain of EGFR. was developed (Cataldo VD, N Engl J Med, 2011, 364, 947).

2nd generation inhibitors

Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations in the gene encoding the epidermal growth factor receptor (EGFR). Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first-generation EGFR-targeting TKIs in approximately half of patients receiving the drug. (Engle JA, Am J Health Syst Pharm 2014, 71 (22), 1933).

Neratinib, a pan-HER inhibitor, an irreversible tyrosine kinase inhibitor, binds to the epidermal growth factor receptor, EGFR (or HER1), HER2 and HER4 and inhibits their tyrosine kinase activity, leading to reduced phosphorylation and downstream signaling pathways. It leads to activation. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being studied in a variety of clinical trials in breast cancer and other solid tumors, including tumors with HER2 mutations (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147).

Dacomitinib is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell line and xenograft studies, dacomitinib has demonstrated activity against both activating EGFR mutations and EGFR T790M (Liao BC, Curr Opin Oncol. 2015, 27(2), 94).

3rd generation inhibitors

Third-generation EGFR-TKIs were designed to inhibit EGFR T790M while preserving wild-type EGFR.

AZD9291 (AstraZeneca, Macclesfield, UK), a mono-anilino-pyrimidine compound, is an irreversible mutant selective EGFR-TKI. This drug is structurally different from first and second generation EGFR-TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFR mutations (EGFR del19 and EGFR L858R) and EGFR T790M. AZD9291 also caused robust and sustained tumor regression in tumor xenografts and transgenic mouse models harboring activating EGFR mutations and EGFR T790M. AZD9291 was less potent in inhibiting phosphorylation in wild-type EGFR cell lines (Liao BC, Curr Opin Oncol. 2015, 27(2), 94).

Rosiletinib (CO-1686) (Clovis Oncology, Boulder, CO), a 2,4-disubstituted pyrimidine molecule, is an irreversible mutant selective EGFR-TKI. In preclinical studies, CO-1686 caused tumor regression in cell lines, xenograft models, and transgenic mouse models harboring activating EGFR mutations and EGFR T790M (Walter AO, Cancer Discov, 2013, 3(12), 1404).

HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, Korea) is an orally administered selective inhibitor for activating EGFR mutations and EGFR T790M. It has low activity against wild-type EGFR (Steuer CE, Cancer. 2015, 121(8), E1).

Hillig et al. 2019 PNAS] describes the following compounds as potent SOS1 inhibitors and as tool compounds for further investigation of RAS-SOS1 biology in vitro:

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FR 3 066 761 (Universite d'Orleans et al.) describes the following compounds for the treatment of cancer:

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WO 2018/134685 (Eisai Management Co. Ltd. et al.) describes the following compounds for the treatment and prevention of filarial infection:

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WO 2018/172250 (Bayer Pharma AG) describes 2-methyl-quinazolines that inhibit Ras-Sos interactions:

.

.

WO 2018/115380 (Boehringer Ingelheim) describes benzylamino substituted quinazolines as SOS1 inhibitors:

.

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WO 2019/122129 (Boehringer Ingelheim) describes benzylaminosubstituted pyridopyrimidinones as SOS1 inhibitors:

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WO 2020/180768 and WO 2020/180770 (Revolution Medicines) describe compounds of the formula as SOS1 inhibitors:

.

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WO 2021/228028 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) describes a compound of the formula as a SOS1 inhibitor:

.

.

Additional interesting documents include:

[Hofmann et al., Cancer Discov 2021;11:142-5] and

[Hillig RC, Bader B. Adv Cancer Res. 2022;153:169-203].

Leading up to the present invention, it has been found that the compounds of the invention have surprising and advantageous properties, which form the basis of the invention.

In particular, the compounds of the present invention have surprisingly been found to effectively and selectively inhibit the Ras-Sos1 interaction and can therefore be used for the treatment or prevention of hyperproliferative disorders, especially cancer.

According to a first aspect, the invention comprises a compound of formula (I): or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof:

here

X ₁ represents CH or N;

X ₂ represents CR ^a or N;

X ₃ represents CR ^a or N;

X ₄ represents CH or N;

Y represents O or S;

R ¹ , R ² are independently selected from C _1-4 alkyl, OR ^b or NR ^c R ^d ; or

R ¹ , R ² together with the phosphorus atom to which they are attached form a 4-7 membered heterocycloalkyl, wherein one or more carbon atoms are -O-, -NR ^e -, -S-, -S(O) -, S(O) ₂ - or -S(O)NR ^f -; wherein each remaining carbon atom may be optionally substituted by 1 or 2 CH ₃ or 1 -CH ₂ -CH ₃ ;

R ³ is selected from -H, -OH, -OMe, -CN, -NR ^p R ^q , or C _1-2 -alkyl optionally substituted with OH, OMe, CN or halogen;

R ⁴ is selected from -F, -Cl, -Br, -OH, -NH ₂ , -N(CH ₃ )H, -CH ₃ or -CF ₂ H;

R ⁵ represents -ABE, where

A represents -CR ^j R ^k - or is absent,

B represents -CR ^l R ^m - or is absent,

E is -H, -F, -OH, -OCH ₃ , -NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -N(CH ₃ )-OCH ₃ , -CN, -SO ₂ - CH ₃ , -NH-SO ₂ -CH ₃ , -N(CH ₃ )-SO ₂ -CH ₃ , -NH-C(O)-CH ₃ , -N(CH ₃ )-C(O)-CH ₃ , -S(=NH)(=O)-CH ₃ , -S(=N-CH ₃ )(=O)-CH ₃ , -C(O)-NH ₂ , -C(O)-NH(CH ₃ ), -C(O)-N(CH ₃ ) ₂ ; or

R ⁵ represents -SO ₂ -NR ⁿ R ^o ;

R ⁶ is selected from -H, halogen or -CH ₃ ;

R ^a is -H, halogen, -OH, -OCH ₃ , -CN, cyclopropyl, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , or halogen, -OH or -OCH ₃ , is selected from -CH ₃ , -CF ₃ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ or C _1-2 alkyl optionally substituted one or more times by -CN;

R ^b is -H (provided that only one R ^b can be H if both R ¹ and R ² are OR ^b ), -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl;

R ^c is selected from -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl,

R ^d is selected from -H, -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl,

R ^e is H, C ₁ -C ₃ -alkyl optionally substituted by one or more F, cyclopropyl, -C(O)-R ^g , -SO ₂ -CH ₃ , or -CH ₃ , halogen, -CF ₃ or 5-membered heteroaryl optionally substituted by -CF ₂ H;

R ^f is selected from H, -CH ₃ , or -CH ₂ -CH ₃ ;

R ^g is selected from -OH, -OCH ₃ , -CH ₃ , C _1-4 alkyl optionally substituted by halogen, or

-CH ₃ , CH ₂ CH ₃ , CF ₂ H, CF ₃ or a 5-membered heteroaryl optionally substituted by halogen, or

is selected from NR ^h R ⁱ ;

R ^h is selected from H or -CH ₃ ;

R ⁱ is selected from C _1-3 alkyl optionally substituted by halogen or from cyclopropyl;

R ^j and R ^k are independently selected from H, F or -CH ₃ or together with the carbon atom to which they are attached they form cyclopropyl;

R ^l and R ^m are independently selected from H, deuterium, or -CH ₃ , -CH ₂ -CH ₃ , cyclopropyl, or

or together with the carbon atom to which they are attached form cyclopropyl;

R ⁿ and R ^o are independently selected from H, or C _1-4 alkyl optionally substituted by -OH, -OCH ₃ ; or

R ⁿ and R ^o together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl optionally containing additional heteroatoms selected from N or O, wherein the carbon atom of said heterocycloalkyl is H or C It may be optionally substituted by _1-4 alkyl, and the C _1-4 alkyl is again halogen, =O, -OH, -OCH ₃ , -NH ₂ , -NH-CH ₃ or -N(CH ₃ ) ₂ and the nitrogen atom of the heterocycloalkyl is optionally substituted with -C(O)-cyclopropyl or -C(O)-C _1-4 -alkyl, both of which are optionally substituted one or more times with F. can be;

R ^p and R ^q are independently selected from H, -CH ₃ or -CH ₂ -CH ₃ .

According to a further aspect, the invention includes compounds of formula (Ia) (subgroup of formula (I) above) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof. do:

here

X ₁ represents CH;

X ₂ represents CR ^a or N;

X ₃ represents CR ^a or N;

X ₄ represents CH or N;

Y represents O;

R ¹ , R ² are independently selected from -CH ₃ , -CH ₂ -CH ₃ or -CH(CH ₃ ) ₂ ; or

R ¹ , R ² together with the phosphorus atom to which they are attached form:

;

;

R ³ is selected from -CH ₃ , -CHF ₂ , -CF ₃ or -Cl;

R ⁴ is selected from -H, -NH ₂ or -CH ₃ ;

R ⁵ is selected from:

-Br,

-CF ₂ -H, -CF ₂ -F, -CF ₂ -CH ₃ , -CF ₂ -CH ₂ -OH, -CF ₂ -CD ₂ -OH, -CF ₂ -CH ₂ -OCH ₃ ,

-CF ₂ -CH(CH ₃ )-OH, -CF ₂ -CH(CH ₂ -CH ₃ )-OH, -CF ₂ -C(CH ₃ ) ₂ -OH, CF ₂ -C(CH ₃ ) ₂ - OCH ₃ , -CF ₂ -CH(CH(CH ₃ ) ₂ )-OH, -CF ₂ -CH(C(CH ₃ ) ₃ )-OH, -CF ₂ -C(CH ₃ )(CH ₂ -CH ₂ -CH ₂ -CH ₃ )-OH,

-CF ₂ -C(=O)-CH(CH ₃ ) ₂ , -CF ₂ -C(=O)-C(CH ₃ ) ₃ ,

-CF ₂ -C(=O)-OH, -CF ₂ -C(=O)-NH ₂ , -CF ₂ -C(=O)-N(CH ₃ ) ₂ , -CF ₂ -C(=O )-NH-CH ₃ ,

-CF ₂ -C(=O)-NH-CH ₂ -CH ₃ , -CF ₂ -C(=O)-NH-cyclopropyl,

-CF ₂ -CH ₂ -NH-SO ₂ -CH ₃ , -CF ₂ -CH ₂ -N(CH ₃ )-SO ₂ -CH ₃ , -CF ₂ -CH ₂ -NH-C(=O)-CH ₃ or -CF ₂ -CH ₂ -N(CH ₃ );

R ⁶ is selected from -H, -CH ₃ , -Fl or -Cl;

R ^a is -H, -CH ₃ , -CH ₂ -CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ -OH, -CH ₂ -O-CH ₃ , -OH, -OCH ₃ or from cyclopropyl being selected;

R ^r is selected from: -H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -phenyl, -C(=O)-H, -C(=O)-CH ₃ , -C (=O)-CH ₂ F, -C(=O)-CH(CH ₃ ) ₂ , -C(=O)-CH(CH ₃ )-OH, -C(=O)-CH(CH ₃ ) -O-CH ₃ ,

-C(=O)-CH ₂ -CN, -C(=O)-CH ₂ -O-CH ₃ ,

-C(=O)-OC(CH ₃ ) ₃ , -C(=O)-O-CH ₂ -CH ₃ ,

-C(=O)-NH ₂ , -C(=O)-N(CH ₃ ) ₂ , -C(=O)-CH ₂ -CHF ₂ , -C(=O)-NH-cyclopropyl,

-C(=S)-CH ₃ , -SO ₂ -CH ₃ ,

;

;

R ^s is selected from -CH ₃ or -CD ₃ ;

R ^t is selected from -H or D.

Justice

The term “substituted” means that one or more hydrogen atoms on a designated atom or group are replaced with a substituted one selected from the indicated group, provided that the normal valency of the designated atom under existing circumstances is not exceeded. Combinations of substituents and/or variables are permitted.

The term “optionally substituted” means that the number of substituents may be equal to or different from zero. Unless otherwise indicated, an optionally substituted group may be substituted with as many optional substituents as can be accommodated by replacing the hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or phosphorus atom. Typically, the number of optional substituents, if present, is 1, 2, 3, 4 or 5, especially 1, 2 or 3.

As used herein, the term "one or more", for example in the definition of a substituent of a compound of formula (I) of the invention, means "1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, In particular it means 1, 2 or 3, and even more particularly 1 or 2".

When a group is substituted in a compound according to the present invention, unless otherwise specified, the group may be mono- or poly-substituted with substituent(s). Within the scope of the present invention, the meanings of all repeatedly described groups are independent of each other. It is possible for the groups in the compounds according to the invention to be substituted by 1, 2 or 3 identical or different substituents, in particular by 1 substituent.

As used herein, an oxo substituent refers to an oxygen atom bonded to a carbon atom or a sulfur atom through a double bond.

The term “ring substituent” means a substituent attached to an aromatic or non-aromatic ring that replaces an available hydrogen atom on the ring.

In the case of a complex substituent consisting of more than one moiety, for example (C ₁ -C ₄ -alkoxy)-(C ₁ -C ₄ -alkyl)-, the position of a given moiety is in any suitable position of the complex substituent. It is possible that the C ₁ -C ₄ -alkoxy moiety is in any of the C ₁ -C ₄ -alkyl moieties of the (C 1 -C 4 -alkoxy)-( _{C 1} -C _{4 -alkyl} )- group. Can be attached to a carbon atom. A hyphen at the beginning or end of such a complex substituent indicates the point of attachment of the complex substituent to the remainder of the molecule. When a ring comprising a carbon atom and optionally one or more heteroatoms, such as for example a nitrogen, oxygen or sulfur atom, is substituted with a substituent, said substituent is bonded at any suitable position on the ring, and the suitable carbon atom and/or or bonded to a suitable heteroatom.

The term “comprising” when used herein includes “consisting of”.

If any item within the text is referred to as “as mentioned herein,” this means that it may be referred to anywhere in the text.

Terms mentioned in the text have the following meanings:

The term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, especially a fluorine, chlorine or bromine atom.

The term “C ₁ -C ₆ -alkyl” refers to a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl. , butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethyl. Propyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, means the group 3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl, or isomers thereof. In particular, the groups are groups having 1, 2, 3 or 4 carbon atoms (“C ₁ -C ₄ -alkyl”), for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl or tert. -butyl groups, more particularly groups having 1, 2 or 3 carbon atoms (“C ₁ -C ₃ -alkyl”), for example methyl, ethyl, n-propyl or isopropyl groups.

_{The term “C 1 -C 6 -hydroxyalkyl ” means} a linear or branched, saturated, Monovalent hydrocarbon groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl , 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2- Methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.

The term “C ₁ -C ₆ -alkylsulfanyl” refers to a linear or branched, saturated group of the formula (C ₁ -C ₆ -alkyl)-S—, where the term “C ₁ -C ₆ -alkyl” is defined above. , monovalent groups such as methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, Isopentylsulfanyl, refers to the hexylsulfanyl group.

The term “C ₁ -C ₆ -haloalkyl” means a linear or branched, saturated group where the term “C ₁ -C ₆ -alkyl” is as defined above and wherein one or more of the hydrogen atoms is identically or differently replaced by a halogen atom. , refers to a monovalent hydrocarbon group. In particular, the halogen atom is a fluorine atom. The C ₁ -C ₆ -haloalkyl groups are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-tri. fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.

The term “C ₁ -C ₆ -alkoxy” refers to a linear or branched, saturated, 1-alkyl group of the formula (C ₁ -C ₆ -alkyl)-O-, where the term “C ₁ -C ₆ -alkyl” is defined above. Groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy refers to a group, or an isomer thereof.

The term “C ₁ -C ₆ -haloalkoxy” refers to a linear or branched, saturated, monovalent C ₁ -C ₆ -alkoxy group, as defined above, in which one or more of the hydrogen atoms is identically or differently replaced by a halogen atom. it means. In particular, the halogen atom is a fluorine atom. Said C ₁ -C ₆ -haloalkoxy groups are, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

The term "C ₂ -C ₆ -alkenyl" contains 1 or 2 double bonds and contains 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("C ₂ -C ₃ -alkenyl refers to a linear or branched, monovalent hydrocarbon group having a "kenyl"), and when said alkenyl group contains more than one double bond, it is understood that it is possible for said double bonds to be separate or conjugated to each other. The alkenyl group is, for example, ethenyl (or “vinyl”), prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl. , but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex. -3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop Pro-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3 -enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl, 3-methylbut-1-enyl, 2-methylbut-1-enyl, 1- Methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3 -Methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3 -enyl, 1-methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1-methylpent-2-enyl, 4- Methylpent-1-enyl, 3-methylpent-1-enyl, 2-methylpent-1-enyl, 1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3- Enyl, 1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1-ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethyl But-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropyl Prop-2-enyl, 2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl, 1-isopropylprop-1-enyl, 3 ,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl or hexa-1,5-dienyl It's awesome. In particular, the group is vinyl or allyl.

The term "C ₂ -C ₆ -alkynyl" refers to a linear or branched, monovalent hydrocarbon containing one triple bond and 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms. refers to a group (“C ₂ -C ₃ -alkynyl”). The C ₂ -C ₆ -alkynyl groups are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl. , but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex. -4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3- Methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3 -ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2- Ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2- Dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl group. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C ₃ -C ₈ -cycloalkyl" refers to a saturated, monovalent, mono- or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7 or 8 carbon atoms ("C ₃ -C ₈ -cyclo means "alkyl"). Said C ₃ -C ₈ -cycloalkyl groups are for example monocyclic hydrocarbon rings, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups, or bicyclic hydrocarbon rings, for example Bicyclo[4.2.0]octyl or octahydropentalenyl.

The term “C ₄ -C ₈ -cycloalkenyl” means a monovalent, mono- or bicyclic hydrocarbon ring containing 4, 5, 6, 7 or 8 carbon atoms and one double bond. In particular, the ring contains 4, 5 or 6 carbon atoms (“C ₄ -C ₆ -cycloalkenyl”). Said C ₄ -C ₈ -cycloalkenyl groups are, for example, monocyclic hydrocarbon rings, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl groups, or bicyclic hydrocarbon rings, For example, bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.

The term “C ₃ -C ₈ -cycloalkoxy” and the term “C ₃ -C ₈ -cycloalkyl” refer to a group having the formula (C ₃ -C ₈ -cycloalkyl)-O-, a saturated, monovalent, mono- or bicyclic group, for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy It means energy.

The term “spirocycloalkyl” refers to a saturated, monovalent bicyclic hydrocarbon group in which two rings share one common ring carbon atom, wherein the bicyclic hydrocarbon group has 5, 6, 7, 8, 9, 10 or 11 carbon atoms. Containing two carbon atoms, it is possible for the spirocycloalkyl group to be attached to the rest of the molecule through any one of the carbon atoms except the spiro carbon atom. The spirocycloalkyl groups include, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, and spiro[3.4]octyl. , spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, or spiro[5.5]undecyl.

The terms “4- to 7-membered heterocycloalkyl” and “4- to 6-membered heterocycloalkyl” each have a total of 4, 5, 6 or 7 or 4, 5 or 6 ring atoms and a series of N , means a monocyclic, saturated heterocycle containing 1 or 2 identical or different ring heteroatoms from O and S, wherein the heterocycloalkyl group is connected to the molecule through any one of the carbon atoms or, if present, the nitrogen atom. It is possible to attach it to the rest of the.

The heterocycloalkyl group may be a 4-membered ring, such as for example azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as for example tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-deoxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as for example tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1 , 4-dioxanyl or 1,2-oxazinanyl, or a 7-membered ring such as, but not limited to, azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl. No.

In particular, “4- to 6-membered heterocycloalkyl” refers to a 4- to 6-membered heterocycloalkyl as defined above containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. -Means heterocycloalkyl. More particularly, “5- or 6-membered heterocycloalkyl” refers to a group having a total of 5 or 6 ring atoms, containing 1 ring nitrogen atom and optionally 1 additional ring heteroatom from the series: N, O. It refers to monocyclic and saturated heterocycle.

The term "5- to 8-membered heterocycloalkenyl" has a total of 5, 6, 7 or 8 ring atoms, 1 or 2 double bonds and 1 or 2 identical bonds from the series: N, O, S. or a monocyclic, unsaturated, non-aromatic heterocycle containing different ring heteroatoms; It is possible for the heterocycloalkenyl group to be attached to the rest of the molecule via either one of the carbon atoms or, if present, the nitrogen atom.

The heterocycloalkenyl group is, for example, 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thia Diazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydroxazolyl or 4H- [1,4] It is thiazinyl.

The term "heterospirocycloalkyl" refers to a bicyclic, saturated heterocycle having a total of 6, 7, 8, 9, 10 or 11 ring atoms, wherein the two rings share one common ring carbon atom, “Heterospirocycloalkyl” contains 1 or 2 identical or different ring heteroatoms from the series: N, O, S; It is possible for the heterospirocycloalkyl group to be attached to the rest of the molecule via any of the carbon atoms other than the spiro carbon atom, or via the nitrogen atom if present.

The heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro [5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro [4.3]octyl, azaspiro[5.5]undecyl, or additional homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]- , Spiro[3.5]-, Spiro[3.6]-, Spiro[4.5]-, and Spiro[4.6]-.

The term "fused heterocycloalkyl" refers to a bicyclic, saturated heterocycle having a total of 6, 7, 8, 9 or 10 ring atoms, wherein two rings share two adjacent ring atoms, and wherein the fused "Heterocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; the fused heterocycloalkyl group is fused through any one of the carbon atoms or, if present, a nitrogen atom. It is possible to attach to the rest of the molecule

The fused heterocycloalkyl groups include, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thia zabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl.

The term "bridged heterocycloalkyl" refers to a bicyclic, saturated heterocycle having a total of 7, 8, 9 or 10 ring atoms, wherein the two rings share two common ring atoms that are not adjacent, and wherein the " A “bridged heterocycloalkyl” contains 1 or 2 identical or different ring heteroatoms from the series: N, O, S; It is possible for the bridged heterocycloalkyl group to be attached to the rest of the molecule via any of the carbon atoms except the spiro carbon atom, or via the nitrogen atom if present.

The cross-linked heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, Azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl Cyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo [3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[ 4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2. 2] It is Decil.

The term “heteroaryl” refers to a ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (“5- to 14-membered heteroaryl” groups), especially 5, 6, 9 or 10 rings. having atoms in the series: monovalent, monocyclic, bicyclic or tricyclic containing at least 1 ring heteroatom from N, O and/or S and optionally 1, 2 or 3 further ring heteroatoms refers to an aromatic ring, which is bonded through a ring carbon atom or optionally through a ring nitrogen atom (if allowed by valency).

The heteroaryl group may be a 5-membered heteroaryl group such as for example thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl. Zolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as for example pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or tricyclic heteroaryl groups such as for example carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group such as for example benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl. , indolizinyl or purinyl; or a 10-membered heteroaryl group such as for example quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

In general, and unless otherwise stated, a heteroaryl or heteroarylene group includes all possible isomeric forms thereof, such as: tautomers about the point of attachment to the rest of the molecule and positional isomers. Accordingly, for some illustrative non-limiting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; Alternatively, the term thienyl includes thien-2-yl and thien-3-yl.

In the text, for example, “C ₁ -C ₆ -alkyl”, “C ₁ -C ₆ -haloalkyl”, “C ₁ -C ₆ -hydroxyalkyl”, “C ₁ -C ₆ -alkoxy” or “ The term "C ₁ -C ₆ ", as used in the context of the definition of "C ₁ -C ₆ -haloalkoxy", represents a finite number of carbon atoms from 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It means an alkyl group having.

Additionally, as used herein, for example in the context of the definition of "C ₃ -C ₈ -cycloalkyl", the term "C ₃ -C ₈ " refers to a finite number of carbon atoms from 3 to 8, i.e. refers to a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms.

When a range of values is given, the range encompasses each value and sub-range within the range.

for example:

"C ₁ -C ₆ " means C ₁ , C ₂ , C ₃ , C 4 , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C _{1 -C 4 ,} C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ encompasses -C ₆ , C ₄ -C ₅ , and C ₅ -C ₆ ;

"C ₂ -C ₆ " means C ₂ , C ₃ , C 4 , C ₅ , C ₆ , C ₂ -C ₆ , C ₂ -C ₅ , C _{2 -C 4 ,} C ₂ -C ₃ , C ₃ - encompasses C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ , and C ₅ -C ₆ ;

"C ₃ -C ₁₀ " means C ₃ , C ₄ , C ₅ , C 6 , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₃ -C ₁₀ , C _{3 -C 9 ,} C ₃ -C ₈ , C ₃ -C ₇ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₁₀ , C ₄ -C ₉ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₁₀ , C ₅ -C ₉ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ inclusive;

"C ₃ -C ₈ " means C ₃ , C ₄ , C ₅ , C 6 , C ₇ , C ₈ , C 3 -C ₈ , C ₃ -C ₇ , C _{3 -C 6} , C _{3 -C 5} , C ₃ -C ₄ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ encompasses -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ ;

"C ₃ -C ₆ " means C ₃ , C ₄ , C ₅ , C 6 , C ₃ -C ₆ , C 3 -C ₅ , C ₃ -C ₄ , C _{4 -C 6 ,} C _{4 -C 5} , and C ₅ -C ₆ ;

"C ₄ -C ₈ " means C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C _{4 -C 8 , C 4} -C ₇ , C ₄ -C ₆ , C _{4 -C 5} , C _{5 -} encompasses C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ ;

"C ₄ -C ₇ " means C ₄ , C ₅ , C ₆ , C ₇ , C ₄ -C ₇ , C 4 -C ₆ , C _{4 -C 5} , C ₅ -C ₇ , C ₅ -C ₆ and encompasses C ₆ -C ₇ ;

“C ₄ -C ₆ ” encompasses C ₄ , C ₅ , C ₆ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ ;

"C ₅ -C ₁₀ "is C ₅ , C ₆ , C 7, C ₈ , C ₉ , C ₁₀ , C _{5 -C 10, C 5 -C 9} , C _{5 -C 8 ,} C _{5 -C 7} , C ₅ -C ₆ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C 7 -C ₉ , C _{7 -C 8} , C ₈ encompasses -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ ;

"C ₆ -C ₁₀ " means C ₆ , C ₇ , C 8 , C ₉ , C ₁₀ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C _{6 -C 7 ,} C ₇ - It encompasses C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ .

As used herein, the term “leaving group” means an atom or group of atoms that is replaced in a chemical reaction by a stable species having bonding electrons. In particular, these leaving groups are halides, especially fluorides, chlorides, bromides or iodides, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl) Sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl] It is selected from the group comprising oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

In the context of the present invention, substituents and moieties have the following meanings, unless otherwise specified:

In the context of the present invention (C ₁ -C ₄ )-alkyl refers to a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms, such as for example methyl, ethyl, n-propyl, isopropyl, n -refers to butyl, isobutyl, sec-butyl and tert-butyl.

(C ₁ -C ₄ )-Alkoxy in the context of the present invention refers to a straight-chain or branched alkoxy group having 1, 2, 3 or 4 carbon atoms, such as for example methoxy, ethoxy, n-propoxy, iso. means propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy.

Mono-(C ₁ -C ₄ )-alkylamino in the context of the present invention refers to an amino group with one straight-chain or branched alkyl substituent containing 1, 2, 3 or 4 carbon atoms, such as for example methylamino. , ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.

Di-(C ₁ -C ₄ )-alkylamino in the context of the present invention refers to an amino group bearing two identical or different straight-chain or branched alkyl substituents each containing 1, 2, 3 or 4 carbon atoms, such as, for example, For example N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-methylamino, N-isopropyl- Nn-propylamino, N,N-diisopropylamino, Nn-butyl-N-methylamino, and N-tert-butyl-N-methylamino.

In the context of the present invention (C ₁ -C ₄ )-alkylcarbonyl refers to a straight chain having 1, 2, 3 or 4 carbon atoms bonded to the remainder of the molecule via a carbonyl group [-C(=O)-]. or branched alkyl groups such as for example acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl and pivaloyl.

In the context of the present invention (C ₁ -C ₄ )-alkoxycarbonyl refers to a straight chain having 1, 2, 3 or 4 carbon atoms bonded to the remainder of the molecule via a carbonyl group [-C(=O)-]. or branched alkoxy groups such as for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

Mono-(C ₁ -C ₄ )-alkylaminocarbonyl in the context of the present invention is bonded to the remainder of the molecule via a carbonyl group [-C(=O)-] and contains 1, 2, 3 or 4 carbon atoms. An amino group with one straight-chain or branched alkyl substituent, such as for example methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl and tert -Means butylaminocarbonyl.

In the context of the present invention di-(C ₁ -C ₄ )-alkylaminocarbonyl is attached to the remainder of the molecule via the carbonyl group [-C(=O)-] and in each case 1, 2, 3 or 4 Amino groups bearing two identical or different straight-chain or branched alkyl substituents having 2 carbon atoms, such as for example N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N- Methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-N-methylaminocarbonyl, N,N-diisopropylaminocarbonyl, Nn-butyl-N-methylaminocarbonyl and It means N-tert-butyl-N-methylaminocarbonyl.

In the context of the present invention (C ₃ -C ₆ )-cycloalkyl refers to monocyclic, saturated carbocycles having 3, 4, 5 or 6 ring carbon atoms, such as: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example, especially cyclopropyl and cyclobutyl,

In the context of the present invention 4- to 7-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl are 1 or ₂ from the series N, O, S, S(O) and (S)(O) 2 containing identical or different ring heteroatoms, which may be bonded through ring carbon atoms or through ring nitrogen atoms (if present), for a total of 4, 5, 6 or 7, or 4, 5 or 6 Monocyclic, saturated heterocycles with ring atoms such as azetidinyl, oxetanyl, thiethanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1- Deoxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 ,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomorpholinyl, 1,1-deoxidothiomorpholinyl, azepanyl, 1,4 -diazepanil, and 1,4-oxazepanil, for example 4, which in particular contains 1 ring nitrogen atom and optionally 1 further ring heteroatom from the series N, O or S(O) ₂ - to 6-membered heterocycloalkyl and 5- or 6-membered heterocycloalkyl containing 1 ring nitrogen atom and optionally 1 further ring heteroatom from the series N or O: for example azetidinyl, pyrroli Dinyl, pyrazolidinyl, imidazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, piperidinyl, piperazinyl, 1,2-oxazinanyl, morpholinyl, and thiomor refers to polynyl, especially pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

A 5-membered aza-heteroaryl in the context of the present invention contains at least 1 ring nitrogen atom and optionally 1 or 2 further ring heteroatoms selected from N, O and S, and is connected via a ring carbon atom or optionally by a ring nitrogen. Aromatic heterocyclic group (heteroaromatic) having a total of 5 ring atoms, bonded via atoms (where allowed by valency), especially 1 ring nitrogen atom and 1 or 2 additional rings selected from N and O 5-membered aza-heteroaryl containing heteroatoms, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, e.g. This refers in particular to pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl.

An oxo substituent in the context of the present invention means an oxygen atom bonded to a carbon atom through a double bond.

It is possible for compounds of formula (I) to exist as isotopic variants. The present invention therefore encompasses one or more isotopic variant(s) of the compounds of formula (I), especially deuterium-containing compounds of formula (I).

The term “isotopic variant” of a compound or reagent is defined as a compound that exhibits a non-natural proportion of one or more isotopes of which such compound is composed.

The term “isotopic variant of a compound of formula (I)” is defined as a compound of formula (I) that exhibits a non-natural proportion of one or more isotopes of which such compound is composed.

The expression “non-natural proportion” means the proportion of such isotope that is higher than its natural abundance. The natural abundance ratio of isotopes applicable in this regard is described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.

Examples of such isotopes are stable radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ respectively. ^C , ¹³ C, ¹⁴ C ^{, 15} N, ¹⁷ O, ¹⁸ O, ³² P, 33 P, 33 S, 34 S, ³⁵ S, ³⁶ S, ¹⁸ F ^{, 36} Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, Includes ¹²⁵ I, ¹²⁹ I and ¹³¹ I.

In the context of the treatment and/or prevention of the disorders specified herein, the isotopic variant(s) of the compounds of formula (I) preferably contain deuterium (“deuterium-containing compounds of formula (I)”). Isotopic variants of compounds of formula (I) incorporating one or more radioactive isotopes, such as ³ H or ¹⁴ C, are useful, for example, in drug and/or substrate tissue distribution studies. These isotopes are particularly desirable due to their ease of incorporation and detection sensitivity. Positron emitting isotopes such as ¹⁸ F or ¹¹ C may be incorporated into compounds of formula (I). These isotopic variants of compounds of formula (I) are useful for in vivo imaging applications. The deuterium-containing and ¹³ C-containing compounds of formula (I) can be used for mass spectrometry analysis in connection with preclinical or clinical studies.

Isotopic variants of a compound of formula (I) are generally prepared by methods known to those skilled in the art, such as those described in the Schemes and/or Examples herein, by producing a reagent, preferably an isotopic variant of the reagent. Alternatively, it can be prepared by substitution with a deuterium-containing reagent. Depending on the desired deuteration site, in some cases deuterium from D ₂ O can be incorporated directly into the compound or into reagents useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic linkages is a rapid route for the incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen in the containing functional groups for deuterium. Various deuteration reagents and synthetic building blocks are available, for example, from C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc. (Princeton, NJ, USA).

The term “deuterium-containing compound of formula (I)” refers to a compound of formula (I) in which one or more hydrogen atom(s) is replaced by one or more deuterium atom(s) and the deuterium at each deuteration position of the compound of formula (I). It is defined as a compound of formula (I) in which the abundance is higher than the natural abundance of deuterium, about 0.015%. In particular, in the deuterium-containing compound of formula (I), the abundance of deuterium at each deuterated position of the compound of formula (I) is 10%, 20%, 30%, 40%, 50% at said position(s). , greater than 60%, 70% or 80%, preferably greater than 90%, 95%, 96% or 97%, even more preferably greater than 98% or 99%. It is understood that the abundance of deuterium at each deuteration site is independent of the abundance of deuterium at the other deuteration site(s).

Selective incorporation of one or more deuterium atom(s) into a compound of formula (I) may affect the physicochemical properties of the molecule (e.g. acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19( 3), 271]) and/or may alter the metabolic profile and cause changes in the ratio of parent compound to metabolite or in the amount of metabolites formed. These changes may lead to specific therapeutic benefits and therefore may be desirable in some situations. Reduced rates of metabolism and metabolic switching, with altered ratios of metabolites, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to the parent drug and metabolites can have important consequences with respect to the pharmacokinetics, tolerability and efficacy of deuterium-containing compounds of formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and enhances the formation of desired metabolites (e.g. nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013 , 26, 410; efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to reduce systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits would include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may lead to lower side effects and improved efficacy depending on the pharmacokinetic/pharmacodynamic relationship of the specific compound. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanakatib (K. Kassahun et al., WO2012/112363) are examples of this deuterium effect. Another case has been reported where a reduced metabolic rate increases drug exposure without altering the systemic clearance rate (e.g. rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs that exhibit these effects may have reduced dosing requirements (e.g., fewer doses or lower dosages to achieve the desired effect) and/or may produce lower metabolite loads. .

Compounds of formula (I) may have multiple potential attack sites for metabolism. In order to optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of formula (I) may be selected that have a specific pattern of one or more deuterium-hydrogen exchange(s). In particular, the deuterium atom(s) of the deuterium-containing compound(s) of formula (I) is attached to a carbon atom and/or is the site of attack for metabolic enzymes, such as for example cytochrome P ₄₅₀ . is located at the location of

When the plural form of the words compounds, salts, polymorphs, hydrates, solvates, etc. is used herein, this is also taken to mean a single compound, salt, polymorph, isomer, hydrate, solvate, etc. do.

“Stable compound” or “stable structure” means a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The compounds of the present invention optionally contain one or more asymmetric centers depending on the position and nature of the various substituents of interest. It is possible for one or more asymmetric carbon atoms to exist in the (R) or (S) configuration, which can give rise to racemic mixtures in the case of a single asymmetric center or diastereomeric mixtures in the case of multiple asymmetric centers. You can. In certain cases, asymmetry may also be present due to limited rotation about a given bond, for example the central bond adjacent to the two substituted aromatic rings of the specified compounds.

Preferred compounds are those that produce more desirable biological activities. Isolated, pure or partially purified isomers and stereoisomeric or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of these materials can be accomplished by standard techniques known in the art.

Preferred isomers are those that produce more desirable biological activities. These isolated, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included within the scope of the invention. Purification and isolation of these materials can be accomplished by standard techniques known in the art.

Optical isomers can be obtained by resolution of racemic mixtures according to customary methods, for example by formation of diastereomeric salts using optically active acids or bases or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereomers can be separated into its individual diastereomers based on their physical and/or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then liberated from the isolated diastereomeric salt. Different methods for the separation of optical isomers involve the use of chiral chromatography (e.g., HPLC columns using chiral phases) with or without conventional derivatization, optimally selected to maximize separation of the enantiomers. . Suitable HPLC columns using chiral phases are commercially available, such as those manufactured by Daicel, for example Chiracel OD and Chiracel OJ, all of which are commercially available. . Enzymatic separations with or without derivatization are also useful. The optically active compounds of the invention can likewise be obtained by chiral synthesis using optically active starting materials.

To distinguish the different types of isomers from each other, see IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the invention, either as a single stereoisomer or as any mixture of such stereoisomers in any ratio, for example (R)- or (S)-isomers. Isolation of single stereoisomers, for example single enantiomers or single diastereomers, of the compounds of the invention is achieved by any suitable state of the art method, such as for example chromatography, especially chiral chromatography.

Additionally, the compounds of the invention may exist as tautomers. For example, any compound of the invention containing an imidazopyridine moiety as a heteroaryl group may be, for example, the 1H tautomer or the 3H tautomer, or even any amount of the two tautomers, i.e. a mixture of It can exist as:

The present invention includes all possible tautomers of the compounds of the invention, either as a single tautomer or as any mixture of such tautomers in any ratio.

Additionally, the compounds of the invention may exist as N-oxides, which are defined as those in which at least one nitrogen of the compounds of the invention is oxidized. The present invention includes all such possible N-oxides.

The invention also includes useful forms of the compounds of the invention, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and/or coprecipitates.

The compounds of the invention may exist as hydrates or as solvates, where the compounds of the invention contain a polar solvent, especially for example water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, such as hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible, respectively. The present invention includes all such hydrates or solvates.

Additionally, it is possible for the compounds of the invention to exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or in the form of a salt. The salt may be any salt, organic or inorganic addition salt, especially any pharmaceutically acceptable organic or inorganic addition salt, which is commonly used in pharmaceuticals or, for example, for isolating or purifying the compounds of the invention. It is used.

The term “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the invention. For example, literature [S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19].

Suitable pharmaceutically acceptable salts of the compounds of the invention include, for example, acid addition salts of the compounds of the invention that are sufficiently basic, for example retaining a nitrogen atom in the chain or ring, such as mineral acids or “mineral acids”; For example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid, or organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid. , butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxide. Roxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, para -Toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthaline disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, It may be an acid addition salt with D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid or thiocyanic acid.

Additionally, other suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium, magnesium or strontium salts, or aluminum or zinc salts. salts, or from ammonia or from organic primary, secondary or tertiary amines having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine , triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine. , N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino- Ammonium salts derived from 1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or quaternary ammonium ions having 1 to 20 carbon atoms. , such as salts with tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

Those skilled in the art will further appreciate that it is possible for acid addition salts of the claimed compounds to be prepared by reacting the compounds with a suitable inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base through various known methods.

The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of such salts in any ratio.

In the text, especially in the experimental section, for the synthesis of the intermediates and examples of the invention, where compounds are referred to in salt form with the corresponding base or acid, they are as obtained by the respective preparation and/or purification method. The exact stoichiometric composition of the salt form is unknown in most cases.

Unless otherwise specified, a suffix to the chemical name or structural formula associated with the salt, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF ₃ COOH", "x Na ⁺ "means a salt form, for example the stoichiometry of the salt form is not specified.

This applies similarly if the synthetic intermediate or example compound or salt thereof is obtained by the described preparation and/or purification methods as a solvate, such as a hydrate, of unknown stoichiometric composition (where defined).

As used herein, the term "in vivo hydrolyzable ester" refers to an in vivo hydrolyzable ester of a compound of the invention containing a carboxy or hydroxy group, e.g., a pharmaceutical that hydrolyzes in the human or animal body to produce the parent acid or alcohol. Refers to an acceptable ester. Pharmaceutically acceptable esters suitable for carboxylic acid include, for example, alkyl, cycloalkyl and optionally substituted phenylalkyl, especially benzyl esters, C ₁ -C ₆ alkoxymethyl esters, for example methoxymethyl, C ₁ -C ₆ alkanoyl. Oxymethyl esters, such as pivaloyloxymethyl, phthalidyl ester, C ₃ -C ₈ cycloalkoxy-carbonyloxy-C ₁ -C ₆ alkyl esters, such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, such as 5-methyl-1,3-dioxolen-2-onylmethyl; and C ₁ -C ₆ -alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl, which esters may be formed at any carboxy group of the compounds of the invention.

In vivo hydrolyzable esters of compounds of the invention containing hydroxy groups include inorganic esters, such as phosphate esters and [alpha]-acyloxyalkyl ethers, and decompose as a result of in vivo hydrolysis of the esters to give the parent hydroxy group. Includes related compounds. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (giving alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (which gives the carbamate), dialkylaminoacetyl and carboxyacetyl. The present invention includes all such esters.

Additionally, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrug” herein refers to a compound which may itself be biologically active or inert, but which is converted (e.g. metabolically or hydrolytically) into a compound according to the invention during its residence time in the body.

According to another embodiment _the invention provides _a compound of formula (I) wherein only one of X _{1 ,} salts, or mixtures thereof.

According to another embodiment the invention includes compounds of formula (I) wherein Y represents O, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to another embodiment the invention relates to a compound of formula (I), wherein R ¹ and R ² are selected from C _1-4 alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof.

을 형성하는 것인 화학식 (I)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.According to another embodiment the present invention provides a compound in which R ¹ and R ² together with the phosphorus atom to which they are attached

Compounds of formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, which form:

According to another embodiment the invention relates to a compound of formula (I), wherein R ³ is selected from C _1-2 -alkyl optionally substituted with 1 to 3 F or a stereoisomer, tautomer, N-oxide thereof. , hydrate, solvate or salt, or mixtures thereof.

According to another embodiment the invention relates to a compound of formula (I) wherein R ⁶ is selected from -F, -Cl, -H or -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, Includes solvates or salts, or mixtures thereof.

According to another embodiment the invention relates to a compound of formula (I), wherein R ^a is selected from -H, -Cl, -CH ₃ , -CF ₃ or -CF ₂ H or a stereoisomer, tautomer, N thereof. -Includes oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment the invention provides a method of formula (I) wherein R ^j and R ^k together with the carbon atom to which they are attached form cyclopropyl, or both are selected from -F, or both -CH ₃ It includes compounds of or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment the invention provides a morpholine or N- wherein R ⁿ and R ^o together with the nitrogen to which they are attached are both optionally substituted with one or two -CH ₃ , -CF ₃ or -CF ₂ H. and compounds of formula (I) that form acetylpiperazine, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

According to another embodiment the invention provides a compound of formula (I) or a stereoisomer thereof, wherein any substituent of the above embodiments may be combined with any other substituent or substituents from one or more of the above embodiments. , tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment, the present invention includes the following compounds:

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine- 4-amine

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine -4-amine

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

1-benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-benzyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1,4 lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidine- 4-amine

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[2,3-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

6-(dimethylphosphoryl)-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrido Mydin-4-amine

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d] Pyrimidin-4-amine

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7 -Dimethylpyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl} amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[ 2,3-d]pyrimidin-4-amine

(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]- 2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol (mixture of diastereomers)

6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 1)

6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 2)

4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-6-(dimethylphosphoryl )-2-methylpyrido[3,4-d]pyrimidin-8-ol

1-Acetyl-4-[8-hydroxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carbaldehyde

1-Ethanethioyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d ]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylquinazolin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluor Roethan-1-ol

1-Acetyl-4-[8-(hydroxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[8-cyclopropyl-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[8-(difluoromethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyri do[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[8-(methoxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-8-ethyl-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino }ethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol (mixture of diastereomers)

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-4-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-3-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-(methanesulfonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4 -d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4-d ]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetic acid

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-N-cyclopropyl-2,2-difluoroacetamide

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N,N-dimethylacetamide

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4 -d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroacetamide

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N-methylacetamide

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoroacetamide

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-N-ethyl-2,2-difluoroacetamide

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N,N-dimethylacetamide

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N-methylacetamide

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-methyl-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(propan-2-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-benzyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

6-(dimethylphosphoryl)-N-{(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl}-2-methylpyrido[3,4-d]pyrimidine -4-amine

N-[(1R)-1-(3-bromo-2-fluorophenyl)ethyl]-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[2,5-dimethyl-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-2,5-dihydro-1H-1lambda ⁵ amino-phosphol-1-one

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoro( ^2H ₂ )ethan-1-ol

1-(4-{[(1R)-1-{3-[1,1-difluoro-2-hydroxy( ^2H ₂ )ethyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ -phospholan-1-one

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoroethane-1-ol

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

2-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluo lophenyl}-2,2-difluoroethane-1-ol

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluorobutan-2-ol (diastereomer 1)

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol (diastereomer 1)

1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (mixture of diastereomers)

1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (diastereomer 1)

1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (diastereomer 2)

1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (mixture of diastereomers)

1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (diastereomer 1)

1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (diastereomer 2)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino )ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (mixture of diastereomers)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 1)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino )ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (mixture of diastereomers)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 3)

(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 4)

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (mixture of diastereomers)

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 1)

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 2)

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 3)

(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 4)

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-2,5-dihydro-1H-1lambda ⁵ amino-phosphol-1-one

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoropropan-2-ol

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol (diastereomer 2)

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluorobutan-2-ol (diastereomer 2)

(2R*)-1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl ]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)

tert-Butyl 4-[2,8-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] Pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxylate

6-(diethylphosphoryl)-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[3,4-d]pyri Mydin-4-amine

1-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

N-{(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido [3,4-d]pyrimidin-4-amine

1-[4-({(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- 1]-1lambda ⁵ amino-phospholan-1-one

6-(diethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine -4-amine

N-{(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine- 4-amine

6-[di(propan-2-yl)phosphoryl]-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3, 4-d]pyrimidin-4-amine

1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1lambda ⁵ amino-phospholan-1-one

1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine- 6-yl]-1lambda ⁵ amino-phospholan-1-one

6-(dimethylphosphoryl)-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3- d]pyrimidin-4-amine

6-[di(propan-2-yl)phosphoryl]-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[ 2,3-d]pyrimidin-4-amine

1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluo Lophenyl}-1,1-difluoro-2-methylpropan-2-ol

1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1lambda ⁵ amino-phos pollan-1-on

1-benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1, 4lambda ⁵ amino-azaphosphinan-4-one

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}quinazolin-4-amine

1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1lambda ⁵ amino-phospholan-1-one

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[3 ,4-d]pyrimidin-4-amine

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-3-methylbutan-2-one

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-3,3-dimethylbutan-2-one

1-(4-{[(1R)-1-{3-[(2R*)-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ amino-phospholan-1-one (diastereomer 1)

1-(4-{[(1R)-1-{3-[(2R*)-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ amino-phospholan-1-one (diastereomer 2)

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (mixture of diastereomers)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (diastereomer 1)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (diastereomer 2)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (mixture of diastereomers)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (diastereomer 1)

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (diastereomer 2)

N-{(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine- 4-amine

N-{(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2 -Methylpyrido[3,4-d]pyrimidin-4-amine

1-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluo Lophenyl}-1,1-difluoro-2-methylpropan-2-ol

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-2,2-difluoroethane-1-ol

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methyl-7-(trifluoromethyl)pyrido [2,3-d]pyrimidin-4-amine

1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidine -6-yl]-1lambda ⁵ amino-phospholan-1-one

1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylquinazolin-6-yl]-1lambda ⁵ amino- Phospholan-1-one

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylquinazolin-4-amine

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[di(propan-2-yl)phosphoryl]-2,7-dimethylpyrido [2,3-d]pyrimidin-4-amine

2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (mixture of diastereomers)

2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (diastereomer 1)

2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (diastereomer 2)

2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (mixture of diastereomers)

2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (diastereomer 1)

2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (diastereomer 2)

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 1)

(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 2)

1-Acetyl-4-(2 _{-methyl-4-{[(1S)-1-[2-methyl-3-(trifluoromethyl)phenyl](2H4} ⁾ ethyl]amino}pyrido[3, 4-d]pyrimidin-6-yl)-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoroethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)phenyl]ethyl}amino)-2-methylpyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2, 3-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d ]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

(R)-1-(4-(2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d] pyrimidin-6-yl)-4-oxido-1,4-azaphosphinan-1-yl)ethan-1-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2S)-2-methoxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2R)-2-hydroxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-fluorocyclopropane-1-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carbonyl}cyclopropane-1-carbonitrile

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(2-methylpropanoyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(methoxyacetyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2R)-2-methoxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-hydroxycyclopropane-1-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2S)-2-hydroxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(oxetane-3-carbonyl)-1,4lambda ⁵ -azaphosphinan-4-one

1-[1-(difluoromethyl)cyclopropane-1-carbonyl]-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl }amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-(3,3-difluorocyclobutane-1-carbonyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl} Amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

3-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine -6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-yl}-3-oxopropanenitrile

1-(cyclopropanecarbonyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-1-(oxetane-3-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-[(2S)-2-hydroxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one

1-[(2R)-2-hydroxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one

1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine -6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carbonyl}cyclopropane-1-carbonitrile

1-(1-fluorocyclopropane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one

1-[1-(difluoromethyl)cyclopropane-1-carbonyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl) Phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-(3,3-difluorocyclobutane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl ]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1-(2-methylpropanoyl)-1,4lambda ⁵ -azaphosphinan-4-one

1-(cyclopropanecarbonyl)-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl ]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-(1-hydroxycyclopropane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one

1-(cyclopropanecarbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-[(2S)-2-methoxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one

1-(methoxyacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4 -d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-[1-(hydroxymethyl)cyclopropane-1-carbonyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl ]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)methanesulfonamide

N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)acetamide

N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylmethanesulfonamide

N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylacetamide

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxamide

N-cyclopropyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ -azaphosphinan-1-carboxamide

N-(2,2-difluoroethyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyri nor[3,4-d]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxamide

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxamide

Ethyl 4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine- 6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate

N,N-dimethyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d ]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxamide

Ethyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6 -yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate

1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-methylphenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine -6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[4-({(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one

(R)-1-(4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 2-methylpyrido[3,4-d]pyrimidin-6-yl)-4-oxido-1,4-azaphosphinan-1-yl)ethan-1-one

1-Acetyl-4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-2-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[2-(difluoromethyl)-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ azaphosphinan-4-one

1-Acetyl-4-[2-chloro-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1, 4lambda ⁵ -azaphosphinan-4-one

N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)methanesulfonamide

N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)acetamide

N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylmethanesulfonamide

N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylacetamide

N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-cyclopropylacetamide

1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[4-({(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- Il]-1-(difluoroacetyl)-1,4lambda ⁵ amino-azaphosphinan-4-one

1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] pyrimidin-6-yl]-1,4 lambda ⁵ -azaphosphinan-4-one

1-(difluoroacetyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazoline-6- 1]-1,4lambda ⁵ -azaphosphinan-4-one

or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

A further embodiment of the invention is a compound of formula ( _I ) or formula (Ia) above, wherein Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein X ₂ represents CR ^a or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, Contains mixtures.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) _above , wherein Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein X ₃ represents CR ^a or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, Contains mixtures.

A further embodiment of the invention is a compound of formula ( _I ) or formula (Ia) above, wherein Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) _above , wherein Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) _above , wherein Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia), wherein Y represents O, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ¹ is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ¹ is -CH ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ¹ is -CH(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ² is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ² is -CH ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ² is -CH(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof.

을 형성하는 것인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ¹ , R ² together with the phosphorus atom to which they are attached

Compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, which form:

을 형성하는 것인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ¹ , R ² together with the phosphorus atom to which they are attached

Compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, which form:

을 형성하는 것인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ¹ , R ² together with the phosphorus atom to which they are attached

Compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, which form:

A further embodiment of the invention relates to a compound of formula (I) or formula (Ia) above, wherein R ³ is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ³ is -CHF ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ³ is -CF ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ³ is -Cl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ⁴ is -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁴ is -NH ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁴ is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention includes a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -Br, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, Contains mixtures.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -F or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. Contains mixtures.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -OH or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CD ₂ -OH or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -OCH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or compound thereof. salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH(CH ₃ )-OH, or a stereoisomer, tautomer, N-oxide, hydrate, solvent thereof. Contains cargo or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH(CH ₂ -CH ₃ )-OH or a stereoisomer, tautomer, N-oxide, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(CH ₃ ) ₂ -OH, or a stereoisomer, tautomer, N-oxide, hydrate, Includes solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(CH ₃ ) ₂ -OCH ₃ or a stereoisomer, tautomer, N-oxide, hydrate thereof. , solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH(CH(CH ₃ ) ₂ )-OH or a stereoisomer, tautomer, N-oxide thereof. , hydrate, solvate or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH(C(CH ₃ ) ₃ )-OH or a stereoisomer, tautomer, N-oxide thereof. , hydrate, solvate or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, or a conformation thereof, wherein R ⁵ is -CF ₂ -C(CH ₃ )(CH ₂ -CH ₂ -CH ₂ -CH ₃ )-OH. Includes isomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the present invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-CH(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide thereof. Includes seeds, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the present invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-C(CH ₃ ) ₃ or a stereoisomer, tautomer, N-oxide thereof. Includes seeds, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-OH or a stereoisomer, tautomer, N-oxide, hydrate, solvent thereof. Contains cargo or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-NH ₂ or a stereoisomer, tautomer, N-oxide, hydrate, Includes solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-N(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide thereof. Includes seeds, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-NH-CH ₃ or a stereoisomer, tautomer, N-oxide, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-NH-CH ₂ -CH ₃ or a stereoisomer, tautomer, N- Includes oxides, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -C(=O)-NH-cyclopropyl, or a stereoisomer, tautomer, N-oxide thereof, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -NH-SO ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide thereof, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -N(CH ₃ )-SO ₂ -CH ₃ or a stereoisomer, tautomer, N thereof. -Includes oxides, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -NH-C(=O)-CH ₃ or a stereoisomer, tautomer, N- Includes oxides, hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₂ -CH ₂ -N(CH ₃ ) or a stereoisomer, tautomer, N-oxide, hydrate, or stereoisomer thereof, tautomer, N-oxide, hydrate, Includes solvates or salts, or mixtures thereof.

A further embodiment of the invention includes a compound of formula (I) or formula (Ia) above, wherein R ⁶ is -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ⁶ is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention includes a compound of formula (I) or formula (Ia) above, wherein R ⁶ is -Fl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ⁶ is -Cl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ^a is -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ^a is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^a is -CH ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ^a is -CF ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ^a is -CHF ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^a is -CH ₂ -OH, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, Contains mixtures.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^a is -CH ₂ -O-CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ^a is -OH, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof. do.

A further embodiment of the invention relates to a compound of formula (I) or formula (Ia) above, wherein R ^a is -OCH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ^a is -cyclopropyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ^r is -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention provides a compound of formula (I) or formula (Ia) above, wherein R ^r is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -CH(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -CH ₂ -phenyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, Contains mixtures.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or thereof. salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or thereof. salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₂ F or a stereoisomer, tautomer, N-oxide, hydrate, solvate thereof. or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide, hydrate thereof. , solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH(CH ₃ )-OH, or a stereoisomer, tautomer, N-oxide, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH(CH ₃ )-O-CH ₃ or a stereoisomer, tautomer, N- Includes oxides, hydrates, solvates or salts, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₂ -CN or a stereoisomer, tautomer, N-oxide, hydrate, solvent thereof. Contains cargo or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₂ -O-CH ₃ or a stereoisomer, tautomer, N-oxide thereof, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-OC(CH ₃ ) ₃ or a stereoisomer, tautomer, N-oxide, hydrate thereof. , solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-O-CH ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide thereof, Includes hydrates, solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-NH ₂ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or compound thereof. salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-N(CH ₃ ) ₂ or a stereoisomer, tautomer, N-oxide, hydrate thereof. , solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-CH ₂ -CHF ₂ or a stereoisomer, tautomer, N-oxide, hydrate, Includes solvates or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=O)-NH-cyclopropyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvent thereof. Contains cargo or salt, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -C(=S)-CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or thereof. salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^r is -SO ₂ -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

인 상기 화학식 (I) 또는 화학식 (Ia)의 화합물 또는 그의 입체이성질체, 호변이성질체, N-옥시드, 수화물, 용매화물 또는 염, 또는 그의 혼합물을 포함한다.A further embodiment of the invention provides that R ^r is

phosphorus compounds of formula (I) or formula (Ia) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ^s is -CD ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention is a compound of formula (I) or formula (Ia), wherein R ^s is -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Includes.

A further embodiment of the invention includes compounds of formula (I) or formula (la) above, wherein R ^t is -H, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. do.

A further embodiment of the invention includes compounds of formula (I) or formula (Ia) above, wherein R ^t is D, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof. .

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein both R ¹ and R ² are -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (Ia) above, wherein R ⁵ is -CF ₃ and R ⁶ is -F or a stereoisomer, tautomer, N-oxide, hydrate, solvate thereof. or salts, or mixtures thereof.

A further embodiment of the invention is a compound of formula (I) or formula (la) above, wherein X ² is N and X ³ is CH, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or Includes mixtures thereof.

In certain further embodiments of the first aspect, the invention comprises combinations of two or more of the embodiments mentioned above under the heading “Further embodiments of the first aspect of the invention”.

The present invention includes any sub-combination of the compounds of formula (I) above within any embodiment or aspect of the invention.

The present invention includes any sub-combination within any embodiment or aspect of the invention of intermediate compounds.

The present invention includes compounds of formula (I) disclosed in the Examples section of the text below.

Compounds according to the invention of formula (I) can be prepared according to Schemes 1 to 12 below. The schemes and procedures described below illustrate the synthetic routes to compounds of formula (I) of the invention and are not intended to be limiting. It will be apparent to those skilled in the art that the transformation sequence as illustrated in Schemes 1 to 12 can be modified in a variety of ways. Accordingly, the transformation sequences illustrated in these schemes are not intended to be limiting. Additionally, interconversion of any substituent, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ or Y can be accomplished before and/or after the exemplified transformation. These modifications may be, for example, introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metalation, substitution or other reactions known to those skilled in the art. These transformations involve introducing functional groups that enable further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, 3 ^rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.

Several routes for preparing compounds of formula (I) are described in Schemes 1 to 12.

The present invention includes intermediate compounds disclosed in the Examples section of the text below.

The present invention includes any sub-combination of the above intermediate compounds within any embodiment or aspect of the invention.

The compounds of formula (I) of the invention may be converted into any of the salts, preferably pharmaceutically acceptable salts, as described herein by any method known to those skilled in the art. Similarly, any salt of a compound of formula (I) of the invention may be converted to the free compound by any method known to those skilled in the art.

The compounds of formula (I) of the invention demonstrate an unexpected and valuable spectrum of pharmacological action. The compounds of the present invention have surprisingly been found to effectively inhibit SOS1, and thus they can be used for the treatment or prevention of diseases in humans and animals, preferably hyperproliferative disorders.

The compounds of the present invention can be used to inhibit, block, reduce, reduce, etc. cell proliferation and/or cell division, and/or produce apoptosis. This method involves administering to a mammal, including a human, in need of treatment a disorder an effective amount of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt, isomer, polymorph, or metabolite thereof, Includes administering hydrates, solvates or esters.

Hyperproliferative disorders include, for example, psoriasis, keloids, and other hyperplasias affecting the skin, benign prostatic hyperplasia (BPH), and solid tumors such as breast, respiratory tract, brain, reproductive, digestive, urinary, and eye cancers. , liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof. These disorders also include lymphoma, sarcoma, and leukemia.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, medulloblastomas, ependymomas, as well as neuroectodermal and pineal tumors.

Tumors of the male reproductive system include, but are not limited to, prostate cancer and testicular cancer.

Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as sarcomas of the uterus.

Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophagus cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variants), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cavity cancer, and squamous cell.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphomas of the central nervous system.

Sarcomas include, but are not limited to, sarcoma of soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

The invention also provides methods of treating angiogenic disorders, including diseases associated with excessive and/or abnormal angiogenesis.

Inappropriate ectopic expression of angiogenesis can be detrimental to the organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331, 1480 ; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Opthalmol. Vis. Sci., 1996, 37, 855], including neovascular glaucoma, psoriasis, retrolenticular fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, and vascular graft restenosis. Additionally, the increased blood supply associated with cancerous and neoplastic tissue promotes growth, leading to rapid tumor expansion and metastasis. Moreover, the growth of new blood and lymphatic vessels in the tumor provides an escape route for regenerating cells, promoting metastasis and subsequent spread of cancer. Accordingly, the compounds of formula (I) of the invention may be used, for example, by inhibiting and/or reducing angiogenesis; Treating any of the above-mentioned angiogenesis disorders by inhibiting, blocking, depressing, reducing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of these cell types and/ Or it can be used for prevention.

These disorders are well characterized in humans, but also exist with similar etiologies in other mammals and can be treated by administering the pharmaceutical compositions of the invention.

The terms “treating” or “treatment” referred to throughout this application are typically used for the management or cure of a subject, for example, to combat, alleviate, reduce, alleviate, or improve the condition of a disease or disorder, such as carcinoma. .

The compounds of the invention can be used in solid tumors of all indications and stages, especially in the treatment and prevention of tumor growth and metastasis, i.e. in the prevention, in particular with or without pre-treatment of tumor growth.

In general, the use of chemotherapeutic and/or anticancer agents in combination with the compounds or pharmaceutical compositions of the invention

1. Provides superior efficacy in reducing tumor growth or even eliminating tumors compared to administration of the agent alone, and/or

2. Provides administration of chemotherapy agents administered in smaller doses, and/or

3. Provides chemotherapy treatment that is well tolerated in patients, with fewer adverse pharmacological complications than those observed with single-agent chemotherapy and certain other combination therapies, and/or

4. Provide treatment of a broader spectrum of different cancer types in mammals, especially humans, and/or

5. Provides higher response rates among treated patients, and/or

6. Provides longer survival times among treated patients compared to standard chemotherapy treatment, and/or

7. Provides longer tumor progression time and/or

8. Compared to known cases where other cancer agent combinations produce antagonistic effects, it will provide efficacy and tolerability results that are at least as good as those of the agents used alone.

In addition, the compounds of formula (I) of the invention can also be used in combination with radiotherapy and/or surgical intervention.

In a further embodiment of the invention, the compounds of formula (I) of the invention may be used to sensitize cells to radiation, i.e. treating the cells with a compound of the invention prior to radiation treatment of the cells may cause the cells to sensitize cells to radiation. renders the cells more susceptible to DNA damage and cell death than in the absence of any treatment with the compound. In one aspect, cells are treated with at least one compound of formula (I) of the invention.

Accordingly, the present invention also provides a method of killing cells, wherein the cells are administered one or more compounds of the present invention in combination with conventional radiation therapy.

The invention also provides a method of rendering cells more susceptible to cell death, wherein the cells are treated with one or more compounds of formula (I) of the invention prior to treatment of the cells to cause or induce cell death. . In one aspect, after treating the cells with one or more compounds of formula (I) of the invention, the cells are treated with at least one compound or at least one method or a combination thereof to inhibit the function of normal cells or It causes DNA damage for the purpose of killing cells.

In another embodiment of the invention, the cells are killed by treating them with at least one DNA damaging agent, i.e., by treating the cells with one or more compounds of formula (I) of the invention to render the cells susceptible to cell death. After digestion, the cells are treated with at least one DNA damaging agent to kill the cells. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapy agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

In other embodiments, cells are killed by treating them with at least one method that causes or induces DNA damage. These methods include activation of a cell signaling pathway that causes DNA damage when the pathway is activated, inhibition of a cell signaling pathway that causes DNA damage when the pathway is inhibited, and induction of biochemical changes in the cell that cause DNA damage. , but is not limited to this. As a non-limiting example, it can inhibit DNA repair pathways in cells, preventing repair of DNA damage and causing abnormal accumulation of DNA damage in cells.

In one aspect of the invention, the compounds of formula (I) of the invention are administered to cells prior to radiation or other induction of DNA damage in the cells. In another aspect of the invention, the compounds of formula (I) of the invention are administered to cells in combination with radiation or other induction of DNA damage in the cells. In another aspect of the invention, the compounds of formula (I) of the invention are administered to cells immediately after radiation or other induction of DNA damage in the cells has begun.

In another aspect, the cells are in vitro cells. In another embodiment, the cells are in vivo cells.

According to a further aspect, the invention provides a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvent thereof, for use in the treatment or prevention of diseases, in particular hyperproliferative disorders. Compounds and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

The pharmaceutical activity of the compounds according to the invention can be explained by their activity as SOS1 inhibitors.

According to a further aspect, the invention provides a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide thereof, for the treatment or prevention of diseases, in particular hyperproliferative disorders, in particular diseases associated with SOS1. , hydrates, solvates and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

According to a further aspect, the invention provides a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate thereof, for the prevention or treatment of diseases, in particular hyperproliferative disorders, in particular diseases associated with SOS1. , solvates or salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

According to a further aspect, the invention relates to a method for the treatment or prevention of a disease, in particular a hyperproliferative disorder, in particular a disease associated with SOS1, comprising a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide thereof, , hydrates, solvates and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

According to a further aspect, the invention provides a pharmaceutical composition, preferably a compound of formula (I) as described above, or Includes the use of stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

According to a further aspect, the invention provides an effective amount of a compound of formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, especially pharmaceutically acceptable salts thereof, or Methods of treating or preventing diseases, particularly hyperproliferative disorders, particularly diseases associated with SOS1, using mixtures thereof.

According to a further aspect, the invention relates to a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt, especially pharmaceutically acceptable salt, or mixture thereof, and pharmaceutical compositions, especially medicaments, comprising one or more excipients, especially one or more pharmaceutically acceptable excipient(s). Conventional procedures can be used to prepare these pharmaceutical compositions into appropriate dosage forms.

The invention also encompasses pharmaceutical compositions, especially medicaments, comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they are administered in a suitable manner, e.g. via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, cutaneous, transdermal, conjunctival, otic route or as implants or stents. may be administered.

For these routes of administration, it is possible for the compounds according to the invention to be administered in suitable dosage forms.

For oral administration, dosage forms known in the art that deliver the compounds of the invention in a rapid and/or modified manner, such as, for example, tablets (uncoated or coated tablets, for example, delayed dissolution or with an insoluble enteric or controlled release coating), orally-disintegrating tablets, films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, It is possible to formulate the compounds according to the invention as emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphous and/or dissolved form into the above dosage forms.

Parenteral administration is performed either avoiding the absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g. intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). It can be. Suitable dosage forms for parenteral administration are in particular preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for other routes of administration include pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; Tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; Eye drops, eye ointments, eye drops, eye inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; Vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, spray powders, implants or stents.

The compounds according to the invention can be incorporated into the dosage forms mentioned. This can be accomplished in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include in particular:

· Fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel® ⁾ , lactose, mannitol, starch, calcium phosphate (e.g. Di-Cafos® ⁾ )),

· Ointment bases (e.g. petroleum jelly, paraffin, triglycerides, wax, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycol),

· Bases for suppositories (e.g. polyethylene glycol, cacao butter, hard fats),

· Solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

· Surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g. ^Lanette® ), sorbitan fatty acid esters (e.g. Span ^® ), polyoxyethylene sorbitan fatty acid esters (such as e.g. Tween ^® ), polyoxyethylene fatty acid glycerides (such as e.g. Cremophor ^® ), polyoxyethylene Fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as e.g. Pluronic® ⁾ ,

· Buffers, acids and bases (e.g. phosphate, carbonate, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

· Isotonic agents (e.g. glucose, sodium chloride),

· Adsorbent (e.g. highly disperse silica),

· Viscosity-increasing agents, gel formers, thickeners and/or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomer, polyacrylic acid (such as for example Carbopol ^® ); alginate, gelatin),

Disintegrants (e.g. modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (e.g. Explotab® ⁾ , cross-linked polyvinylpyrrolidone, croscarmellose-sodium (e.g. AcDiSol ^® )),

· Flow regulators, lubricants, glidants and mold release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silica (e.g. ^Aerosil® )),

· Coating materials for films (e.g. sugars, shellac) and film formers or diffusion membranes that dissolve quickly or in a modified manner (e.g. polyvinylpyrrolidone (e.g. Kollidon ^® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit. (Eudragit) ^® )),

· Capsule materials (e.g. gelatin, hydroxypropylmethylcellulose),

· Synthetic polymers (e.g. polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g. Eudragit ^® ), polyvinylpyrrolidone (e.g. Kolidone ^® ) , polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and its copolymers and block copolymers),

· Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate),

· Penetration enhancer,

· Stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

· Preservatives (e.g. parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

· Colorants (e.g. inorganic pigments such as iron oxide, titanium dioxide),

· Flavoring, sweetening, flavor- and/or odor-masking agents.

The invention also relates to pharmaceutical compositions comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipient(s), and their use according to the invention.

According to another aspect, the invention provides at least one compound of formula (I) of the invention and at least one further active ingredient, especially for the treatment and/or prevention of hyperproliferative disorders, in particular diseases associated with SOS1. Pharmaceutical combinations comprising, particularly medicaments, include.

In particular, the present invention includes pharmaceutical combinations comprising:

· at least one first active ingredient, in particular a compound of formula (I) as defined above, and

· One or more additional active ingredients suitable for the treatment of hyperproliferative disorders, especially diseases associated with SOS1.

In the present invention, the term “combination” is used as is known to those skilled in the art, and the combination may be a fixed combination, a non-fixed combination, or a kit of parts.

In the present invention a “fixed combination” is used as is known to a person skilled in the art and includes, for example, a first active ingredient, such as one or more compounds of formula (I) of the invention, and further active ingredients. It is defined as a combination that exists together in one unit dose or as one single entity. An example of a “fixed combination” is a pharmaceutical composition in which a first active ingredient and a further active ingredient are present in a mixture, such as in a formulation, for simultaneous administration. Another example of a “fixed combination” is a pharmaceutical combination in which the first active ingredient and additional active ingredients exist as one unit without being mixed.

Non-fixed combinations or “kits of parts” in the present invention are used as known to those skilled in the art and are combinations in which the first active ingredient and the further active ingredient are present in more than one unit. is defined. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the additional active ingredient are present separately. It is possible for the components of a non-fixed combination or kit of parts to be administered individually, sequentially, simultaneously, jointly or staggered.

The compounds of the invention may be administered as sole pharmaceutical agents or in combination with one or more other pharmaceutically active ingredients provided that the combination does not cause unacceptable adverse effects. The present invention also includes such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known anticancer agents.

Examples of anticancer agents include:

131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, Alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, Ancestim, Anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arsitumomab, arglavine, arsenic trioxide, asparaginase, atezolizumab, avelumab, Axicaptagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, becilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleo Mycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium foliate, calcium levofolinate, caffein Cytabine, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, selmoryukin, cemiplimab, ceritinib, cetuk. Cimab, chlorambucil, chlormadinone, chlormetine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, chrysantaspase, chryzo Tinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, darolutamide, dasatinib, daunorubicin, decitabine, dega Relix, Denileukin Diftitox, Denosumab, Defreotide, Deslorelin, Dianhydrogalactitol, Dexrazoxane, Dibrospidium Chloride, Dianhydrogalactitol, Diclofenac, Dinutuximab, Docetaxel, Dola Cetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, endostatin, eno Cytabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine , ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, polline. Acids, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, meglumine gadoterate, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, Gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indicetron, incadronic acid, ingenol Mebutate, inotuzumab ozogamicin, interferon alpha, interferon beta, interferon gamma, iobenguan (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, Lanreotide, lansoprazole, lapatinib, iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisurid, Lobaplatin, lomustine, ronidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mephitiostane, mercaptopurine, mesna, methadone, methotrexate , methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metyrosine, midostaurin, mifamurtide, miltefosine, myriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, Mitoxantrone, mogamulizumab, molgramostim, furidamole, morphine hydrochloride, morphine sulfate, Embasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nesi Tumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimu Steen, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxin mephesuccinate, omeprazole, ondansetron, ofrelbechin, orgoteine , orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panidamine. Tumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, Pembrolizumab, pemetrexed, pentazocine, pentostatin, peflomycin, perflubutane, perfosfamide, pertuzumab, picivanil, pilocarpine, pirarubicin, pixantrone, plerixapor, plicama Isin, polyglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, Procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, raspuri. Case, razoxan, lefametinib, regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romultide, rucaparib. , Samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizopyran, sobuzoxan, sodium glycididazole, sonidegib, sorafenib , stanozolol, streptozocin, sunitinib, talaporphine, thalimogen laherparepbec, tamibalotene, tamoxifen, tapentadol, tasonermin, tesseleukin, technetium (99mTc), nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + otheracil, temoporphine, temozolomide, temsirolimus, teniposide, testosterone, tetrophosmine , thalidomide, thiotepa, thymalfacin, thyrotropin alfa, thioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol. , Trastuzumab, Trastuzumab Emtansine, Treosulfan, Tretinoin, Trifluridine + Tipiracil, Trilostane, Triptorelin, Trametinib, Trophosphamide, Thrombopoietin, Tryptophan, Ubenimex, Valala Tinib, Valrubicin, Vandetanib, Vapreotide, Vemurafenib, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorinostat, Vorozol, Yttrium-90 Glass Micro Spheres, genostatin, genostatin stimalamer, zoledronic acid, and zorubicin.

Based on known standard laboratory techniques for evaluating compounds useful for the treatment of hyperproliferative general disorders, by standard toxicological tests and standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and with the results of these By comparison with the results of known active ingredients or medicaments used to treat these conditions, effective dosages of the compounds of the invention can be readily determined for the treatment of each desired indication. The amount of active ingredient administered in the treatment of either of these conditions varies widely, depending on considerations such as the specific compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated. may vary significantly.

The total amount of active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. A clinically useful dosing schedule would range from 1 to 3 dosing per day to once every 4 weeks. Additionally, a “drug holiday” in which the drug is not administered to the patient for a certain period of time is possible, beneficial to the overall balance between pharmacological effect and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered more than once per day or less than once per day. The average daily dosage for administration by use of injection, and infusion techniques, including intravenous, intramuscular, subcutaneous and parenteral injection, will preferably be 0.01 to 200 mg/kg total body weight. The average daily rectal dosage regimen will preferably be 0.01 to 200 mg/kg total body weight. The average daily vaginal dosage regimen will preferably be 0.01 to 200 mg/kg total body weight. The average daily topical dosage regimen will preferably be 0.1 to 200 mg administered 1 to 4 times per day. The transdermal concentration will preferably be that required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be 0.01 to 100 mg/kg total body weight.

Of course, the specific initial and continuous dosing regimen for each patient will depend on the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, route of administration, and drug excretion. It will vary depending on speed, drug combination, etc. The desired treatment mode and frequency of administration of the compound of the present invention or its pharmaceutically acceptable salt or ester or composition can be confirmed by a person skilled in the art using routine therapeutic tests.

experimental section

NMR peak shapes are stated as they appear in the spectrum, and possible higher order effects are not considered.

¹ H-NMR data of selected compounds are listed in the form of ¹ H-NMR peak list. Here, δ values (ppm) are given for each signal peak, followed by signal intensity reported in round brackets. δ value-signal intensity pairs from different peaks are separated by commas. Therefore, the peak list is written by the following general form: δ ₁ (intensity ₁ ), δ ₂ (intensity ₂ ), ... , δ _i (intensity _i ), ... , δ _n (intensity _n ) .

The intensity of the sharp signal is correlated with the height (cm) of the signal in the printed NMR spectrum. When compared to other signals, this data can be correlated to an actual percentage of signal strength. For broad signals, more than one peak, or center of the signal, is displayed along with its relative intensity compared to the strongest signal appearing in the spectrum. ^{The 1} H-NMR peak list is similar to a typical ¹ H-NMR reading and therefore typically includes all peaks listed in a typical NMR analysis. Additionally, similar to a typical ¹ H-NMR output, the peak list may represent solvent signals, signals derived from stereoisomers of a particular compound of interest, peaks of impurities, ¹³ C satellite peaks, and/or rotational sidebands. The peaks of stereoisomers and/or impurities typically appear at lower intensities compared to the peaks of the target compound (e.g., >90% purity). These stereoisomers and/or impurities may be typical of a particular manufacturing method, and thus their peaks can help confirm the reproducibility of the manufacturing method based on the "by-product fingerprint". The expert calculates the peak of the target compound by known methods (by MestReC, ACD simulation, or by use of experimentally evaluated expectations), optionally using additional intensity filters, to determine the peak of the target compound as necessary. It can be isolated. This performance will be similar to peak-selection in a typical ¹ H-NMR analysis. For a detailed description of reporting NMR data in peak list format, see the publication ["Citation of NMR Peaklist Data within Patent Applications" (http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014]). In the peak selection routine as described in Study Disclosure Database No. 605005, the parameter “minimum height” can be adjusted from 1% to 4%. However, depending on the chemical structure and/or the concentration of the compound measured, it may be reasonable to set the parameter “minimum height” to <1%.

Chemical names were generated using ACD/Nomenclature software from ACD/Labs. In some cases, the generally accepted names of commercially available reagents were used in place of the ACD/name generated names.

Table 1 below lists abbreviations used in this paragraph and in the Examples section unless explained within the text. Other abbreviations have their meanings which are customary to those skilled in the art.

Table 1: Abbreviations

The table below lists the abbreviations used herein.

Other abbreviations have their meanings which are customary to those skilled in the art.

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

The example test experiments described herein serve to illustrate the invention, and the invention is not limited to the examples given.

Experimental Section - General Section

All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or can be formed from known compounds by methods known to those skilled in the art.

Compounds and intermediates prepared according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, compounds can be purified by crystallization. In some cases, impurities can be removed using a suitable solvent. In some cases, the compounds are purified by chromatography, in particular, for example, by using prepacked silica gel cartridges, such as Biotage SNAP cartridges KP-Sil ^® or KP-NH ^{® ,} on a Biotage purifier system (SP4 ^® or Isolera (Isolera Four) ^® ) and an eluent such as hexane/ethyl acetate or DCM/methanol. In some cases, the compounds can be purified using, for example, a Waters purifier equipped with a diode array detector and/or an on-line electrospray ionization mass spectrometer, a suitable prepacked reversed-phase column, and additives such as trifluoroacetic acid. , eluents that may contain formic acid or aqueous ammonia, such as water and acetonitrile, in combination with a gradient of acetonitrile.

In some cases, purification methods as described above can be used to purify compounds of the invention in the form of salts, such as in the case of sufficiently basic compounds of the invention, for example in the form of trifluoroacetate or formate salts, or for compounds of the invention that are sufficiently acidic. In some cases, it is possible to provide compounds of the invention bearing sufficiently basic or acidic functional groups, for example in the form of ammonium salts. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or can be used as salts in subsequent biological assays. It should be understood that a particular form (e.g., salt, free base, etc.) of a compound of the invention as isolated and described herein is not necessarily the only form in which the compound can be applied in a biological assay to quantify a particular biological activity. .

Experimental Section - General Procedure

Compounds of the invention may be prepared as described in the sections below. The schemes and procedures described below illustrate the general synthetic route to the compounds of formula (I) of the invention and are not intended to be limiting. It will be apparent to those skilled in the art that the transformation sequence as illustrated in the scheme may be modified in a variety of ways. Accordingly, the transformation sequences illustrated in the schemes are not intended to be limiting. Additionally, interconversion of any substituents can be accomplished before and/or after the exemplified transformations. These modifications may be, for example, introduction of protecting groups, cleavage of protecting groups, exchange of functional groups, reduction or oxidation, halogenation, metalation, substitution or other reactions known to those skilled in the art. These transformations involve introducing functional groups that enable further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4'" edition, Wiley 2006) ). Specific examples are described in the subsequent paragraphs. Additionally, as is well known to those skilled in the art, two or more consecutive steps, for example " A “one-pot” reaction can be performed.

The synthesis of the compounds of the present invention is preferably carried out according to the general synthesis sequence shown in Schemes 1-12.

Scheme 1

Scheme 1: Synthetic route for _the preparation of compounds of formula ( _IX ⁾ , where X ₁ , ), halide, preferably chloro, bromo, and R ^b * represents a protecting group. R ^b * can be, for example (but not limited to) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl. R ³ is for example (but not limited to) H, (fluorinated) alkyl. LG represents leaving groups as shown, such as for example halides, preferably chloro, alkylsulfonyl, alkylsulfonate, and arylsulfonate.

Step 1 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: In the first step, the halogen-substituted benzoic acid derivatives of formula (II) (which may be commercially available or described in the literature) are prepared by analogy to literature procedures to form the corresponding bicyclic pyrimidine (IX). can be converted to Typically, derivative (II) is reacted with ammonia, preferably under elevated temperature, optionally under high pressure, in water or an organic solvent or mixtures thereof such as for example 1,2-dichloroethane, THF, methanol, ethanol to give formula (III) ) to form a derivative of See, for example, WO2017069275, US20030199511 and US20030187026 and references therein. Alternatively, derivative (II) can be converted to the corresponding acid chloride using for example thionyl chloride, oxalyl chloride in an organic solvent, optionally at elevated temperature, optionally using a drop of DMF. You can. The corresponding acid chlorides are prepared using a metal-catalyzed reaction, optionally in the presence of a ligand, at elevated temperature in an organic solvent such as for example DMF, toluene, 1,4-dioxane/water, in the presence or absence of DMAP, It may be treated with imidamide or a salt thereof and an inorganic base such as cesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as triethylamine, diisopropylethylamine or pyridine. For example, WO2007134986, Bioorg. Med. Chem. Lett., 2015, 23, 3013] and references therein.

Step 2 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, amino substituted benzoic acid derivatives of formula (III) (which may be commercially available or described in the literature) are prepared by analogy to literature procedures to form the corresponding bicyclic pyrimidine (IX) can be converted to Typically, derivative (III) is reacted with acetamidine or imidamide, optionally with a base such as for example potassium carbonate or sodium hydroxide or triethylamine, diisopropylethylamine, at elevated temperature in an organic solvent such as for example DMF. React with 1,8-diazabicyclo[5.4.0]undec-7-ene or pyridine. For example, WO2004071460, WO2015155306 and Chem. Med. Chem., 2014, 9, 2516].

Step 3 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, halogen substituted benzoic acid ester derivatives of formula (IV) (which may be commercially available or described in the literature) can be converted to the corresponding bicyclic pyrimidine IX in analogy to the literature. You can. Typically, derivative (IV) is reacted with or without DMAP using a metal-catalyzed reaction, optionally in an organic solvent such as for example DMF, toluene, 1,4-dioxane/water at elevated temperature, optionally in the presence of a ligand. imidamide or a salt thereof, an inorganic base such as for example cesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4 .0] It can be reacted with undec-7-ene or pyridine. For example, see Chem. Commun., 2008, 6333; Bioorg. Med. Chem. Lett., 2013, 23, 3325]; See WO2018118735, WO2007134986 and their references.

Step 4 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, amino substituted benzoic acid ester derivatives of formula (V) (which may be commercially available or described in the literature) can be prepared by analogy to literature procedures to form the corresponding bicyclic pyrimidine (IX ) can be converted to . Typically, derivative (V) is reacted with nitrile, carboxylic acid chloride, carboxylic acid chloride, carboxylic acid chloride at elevated temperature in water or organic solvent, or mixtures thereof, such as for example DMF, toluene, 1,4-dioxane/water, in the presence of acid or base. It can be reacted with boxylic acid anhydride, imidamide, or a salt thereof. For example, see J. Med. Chem., 2018, 61, 3389; J. Med. Chem., 2019, 62, 9772]; See WO2004071460, WO2007134986 and their references.

Step 5 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, benzoxazinone derivatives of formula (VI) (which are commercially available or can be prepared analogously to literature procedures) can be prepared analogously to literature procedures by forming the corresponding bicyclic pyrimidine ( IX) can be converted to Typically, derivative (VI) can be reacted with ammonium acetate in an organic solvent at elevated temperature. For example, see J. Med. Chem., 2019, 62, 9772; J. Med. Chem., 2011, 54, 6734; Bioorg. Med. Chem., 2014, 22, 5487] or WO2005105760 and references therein.

Step 6 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, benzoic acid amide derivatives of formula (VII) (which may be commercially available or described in the literature) are converted to the corresponding bicyclic pyrimidine (IX) analogously to literature procedures. It can be. Typically, derivative (VII) can be reacted with a base such as sodium hydroxide at elevated temperature in a solvent such as water. For example, Monatshefte Fuer Chemie, 1987, 118, 399; WO2007134986, WO2013016999; See WO2012028578 and its references.

Step 7 → Formula (IX) (Scheme 1)

Bicyclic pyrimidine formation: Alternatively, amino benzoic acid amide derivatives of formula (VIII) (which may be commercially available or described in the literature) are converted to the corresponding bicyclic pyrimidine (IX) similarly to literature procedures. can be converted. Typically, the derivative (VIII) is reacted with an organic acid, organic acid amide or carboxylic acid anhydride at elevated temperature, or optionally with a base, water or organic solvent or mixtures thereof, using a copper-catalyzed reaction, preferably at elevated temperature. You can do it. For example, see Eur. J. Org. Chem., 2020, 2730; Polish Journal of Pharmacology and Pharmacy, 1985, 37, 541; Heterocycles, 2015, 90, 857; Yakugaku Zasshi, 1977, 97, 1022] and references therein.

Step (IX) → (X) (Scheme 1)

Conversion of hydroxyl group to leaving group

In the next step (Scheme 1), compound (IX) can be converted to the corresponding derivative (X) bearing a leaving group (LG), analogously to literature procedures.

When LG = chloro or bromo, typically phosphorus oxytrichloride or phosphorus oxytribromide respectively, with or without N,N-dimethylaniline or N,N-diisopropylethylamine, in organic solvents such as e.g. Used at elevated temperatures in the presence or absence of toluene. For example, US2012/53174; See WO2012/30912 or WO2012/66122 and references therein.

When LG = 2,4,6-triisopropylbenzenesulfonate, typically 2,4,6-triisopropylbenzenesulfonyl chloride, a base such as for example triethylamine and/or DMAP, an organic solvent , for example in dichloromethane. See, for example, WO2010/99379, US2012/53176 and references therein.

When LG = tosylate, typically 4-methylbenzene-1-sulfonyl chloride, a base such as for example triethylamine or potassium carbonate and/or DMAP is used in an organic solvent such as for example dichloromethane or acetonitrile. do. For example, see Org. Lett., 2011, 4374] or [Bioorg. Med. Chem. Lett., 2013, 2663] and references therein.

When LG = trifluoromethanesulfonate, typically N,N-bis(trifluoromethylsulfonyl)aniline or trifluoromethanesulfonic anhydride, a base such as for example triethylamine or 1,8-dia. Zabicyclo[5.4.0]undec-7-ene and/or DMAP are used in an organic solvent such as for example dichloromethane. For example, see J. Am. Chem. Soc., 2015, 13433] or WO2014/100501 and references therein.

Scheme 2

Scheme 2: Synthetic route for the preparation of compounds of formula (I), wherein R ^a * represents a leaving group, such as (but not limited to) a halide, preferably chloro or bromo, and R ^c * represents the protection of R ⁵ represents the derivative. R ^d * and R ^e * are R ¹ and R ² as in formula (I) or their (protected) derivatives. R ^f * is H or a leaving group such as for example chloro. LG represents a leaving group such as for example a halide, preferably chloro, alkylsulfonyl, alkylsulfonate or arylsulfonate, as shown in Scheme 1.

Compounds of formula (XII) are well known in the public domain and can be formed from compounds of formula (IX) and compounds of formula (XI) using dehydration conjugation methods. This method uses coupling reagents such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( pyBOP), which is known to be used in literature [J. Org. Chem., 2007, 72, 10194; Advanced Synthesis & Catalysis, 2018, 360, 4764; Bioorg. Med. Chem., 2019, 27, 931; Refer to the teachings of [WO 2011028741 A1]; It is known in the public domain.

Alternatively, compounds of formula ( or LG = Br using phosphorus oxytribromide, or typically 4-methylbenzene-1-sulfonyl chloride, a base such as for example triethylamine or in an organic solvent such as for example dichloromethane or acetonitrile. Converted using potassium carbonate and/or DMAP to the compound of formula (X) where LG = tosylate. For example, see Org. Lett., 2011, 4374] or [Bioorg. Med. Chem. Lett., 2013, 2663] and references therein.

Subsequently, a compound of formula (X) can be prepared using a nucleophilic substitution reaction (S _N Ar) with a compound of formula ( It can be converted to the compound of XII).

Compounds of formula (XIV) can be formed from compounds of formula (XII) together with compounds of formula (XIII) using literature-known methods. Compounds of formula (XIII) are well known in the public domain, are commercially available, or can be synthesized by known synthetic routes. For example (but not limited to) when R ^f * is H, a metal catalyzed reaction can be performed. For example, US2019/270704, 2019, A1; US2015/225436, 2015, A1 or [J. Med. Chem. 2020, 63, 7081] and the teachings of references therein. When R ^f * is a leaving group (but is not limited to) such as for example chloro, a nucleophilic substitution reaction can be performed. For example, WO2008/110611, 2008, A1 or J. Med. Chem. 2020, 63, 7081] and references therein.

Subsequently, compounds of formula (XIV) can be converted to compounds of formula (I) by using standard, well-documented methods, such as (but not limited to) functional group manipulation. For example (but not limited to) if R ^c * is a protected derivative of R ⁵ in formula (I), removal of the protecting group may be performed. Further functional group manipulations for R ^d * and R ^e * can be performed analogously to the literature, see for example J. Med. Chem. 2020, 63, 7081] and references therein.

For Y = S, see for example CN109776607, 2019, A or Synthesis 2020, 52, 141.

Scheme 3

Scheme ₃ : Synthetic ^route for _the ^{preparation of} compounds of formula ( _{XVI )} , wherein has the meaning given for formula (I) above. R ^c * is R ⁵ or a protected derivative of R ⁵ as in formula (I).

The reaction shown in Scheme 3 can be carried out using different chemistries known to those skilled in the art.

For example, commercially available compound (A1) can be converted to compound (A2) by known procedures (see, for example, WO2008/130021, 2008, A2). Compound (A2) can be cyclized to compound (A3) as described in Scheme 1. Compound (A4) can be obtained from compound (A3) by nucleophilic aromatic substitution (SnAr) at RT to NaSMe in an organic solvent such as for example DMSO (e.g. US2014/336190, 2014, A1, Tetrahedron , 2002, 58, 4931, WO2010/24451, 2010, A1). Compounds of formula (XV) can be obtained from compound A4 as described in Scheme 2. Compounds of formula (XV) can be converted to compounds of formula (XVI) using a variety of chemistries known to those skilled in the art. For example, palladium-catalyzed reactions (see e.g. WO2012/52167, 2012, A1), nucleophilic aromatic substitution (see e.g. WO2012/52167, 2012, A1) or oxidation/nucleophilic aromatic substitution steps ( For example, see KR2016/37198, 2016, A) can be performed. Compounds of formula (XVI) can be converted to compounds of formula (I) as described in Scheme 2.

Scheme 4

Scheme 4: Synthetic route for the preparation of compounds of formula (XII), where R ^a * is P(O)R ^d *R ^e * as shown in Scheme 2 or a leaving group such as (but not limited to) a halide. , preferably chloro or bromo, and R ^c * is R ⁵ as in formula (I) above, or a protected derivative of R ⁵ .

Compounds of formula (XVIII) are well known in the public domain, commercially available, or are heteroaromatics by known synthetic routes, for example, via reaction of compounds of formula (XVII) with urea under different conditions. Formation of rings (see, e.g., the teachings of Luo et al., CN 102584828) or Brogi et al., J. Med. Chem., 2018, 61, 2124; It can be synthesized through a multi-step synthesis as exemplified in the teachings of Bergeron et al., WO 2010014939 A1.

The conversion of compounds of formula (XVIII) to compounds of formula (XIX) is well known in the public domain. For example, when LG = chloro, typically at elevated temperatures, in the presence or absence of N,N-dimethylaniline or N,N-diisopropylethylamine, in the presence or absence of an organic solvent such as for example toluene. Trichlorophosphate or thionyl chloride may be used. See, for example, Cantin et al., Bioorg. Med. Chem. Lett., 2012, 2565; Bayrakdarian et al., WO 2008136756 A1; Luo et al., CN 102584828; Zhou et al., J. Med. Chem., 2015, 58, 9480.

When LG = bromo, phosphorus oxytribromide can be used in the presence or absence of a base and in the presence or absence of an organic solvent such as for example toluene, typically at elevated temperatures. See, for example, Kim et al., J. Org. Chem., 2004, 69, 5638.

The conversion of compounds of formula (XIX) to compounds of formula (XX) using compounds of formula (XI) is well known in the public domain and is similarly illustrated for the conversion of (X) to (XII) in Scheme 2. do. These nucleophilic substitutions have been widely documented, for example [Liwicki et al., WO 2018066718 A1; Gelin et al., WO 2013016197 A1; Jiang, et al., J. Med. See the teachings of Chem., 2016, 59, 10498.

Compounds of formula (XX) can be prepared by different synthetic methods, such as, for example, Suzuki reaction (Liwicki et al., WO 2018066718 A1; Pulipati, et al., Synth. Commun., 2017, 47, 1142), Stille reaction (Johnson et al., WO 2011028741 A1; Labadie et al., Bioorg. Med. Chem. Lett., 2013, 23, 5923) or other methods may be used to convert to the compound of formula (XII), as described in Finlay et al. al., ACS Med. Chem. See the teachings of Letters, 2016, 7, 831.

The remaining steps from compounds of formula (XII) to compounds of formula (I) in Scheme 4 follow the same route and method as described in Scheme 2.

Amine synthesis

Scheme 5

Scheme 5: Synthetic route for the preparation ^{of compounds} of formula ( _XXV ⁾ , wherein It is a protected derivative of R ⁵ .

Step (XXI) → (XXII) (Scheme 5)

In the first step (Scheme 5), the bromo derivative (XXI) (commercially available or described in the literature) can be converted to the corresponding acetyl compound (XXII) by analogy to numerous literature procedures. For example, the reaction can be carried out using different chemistries known to those skilled in the art, for example, by adding an aryl magnesium Grignard reagent to Weinreb amide to form magnesium in an organic solvent such as THF. Grignard chemistry using; Alternatively, it can be performed using palladium catalyzed chemistry or still chemistry. This transformation is described in Grignard: Fillon et al., Tetahedron 2003, 59, 8199; Leazer et al., Org. Synth. 2005, 82, 115; Palladium: WO2005/5382; Stille: WO2019/122129] and the teachings of references therein.

Step (XXII) → (XXIII) (Scheme 5)

The acetyl derivative (XXII), which is commercially available, described in the literature or prepared from (XXI), can be converted to the corresponding chiral sulfinimine (XXIII) by analogy to numerous literature procedures. For example, the reaction can be carried out at ambient temperature using titanium(IV) ethoxide or titanium(IV) isopropoxide in an organic solvent such as, for example, THF. For example, see Chem. Rev. 2010, 110, 3600-3740; Chem. Soc. Rev. 2009, 38, 1162-1186; Tetrahedron 2004, 60, 8003] or WO2019/122129 and references therein.

Step (XXIII) → (XXIV) (Scheme 5)

(R)-Sulfinimine (XXIII) can be converted to the corresponding (R)-sulfinamide (XXIV) analogously to a number of literature procedures. For example, the reaction can be carried out using a reducing agent, for example sodium borohydride or borane-THF, in an organic solvent such as for example ethanol, methanol or THF. Such transformations are known to those skilled in the art and are described in Pan et al., Tetrahedron Asym., 2011, 22, 329; WO2019/122129; Li et al., Chem. Med. Chem., 2018, 13, 1363; Ghosh et al., Eur. J. Med. See the teachings of Chem., 2018, 160, 171. Alternatively, the reaction can be carried out in an aprotic solvent, such as toluene, using a reducing agent such as, for example, diisopropylaluminum hydride. Such conversions are known to those skilled in the art, and are described in WO2017/6282; See the teachings of Lee et al., Synlett., 2019, 30, 401. Alternatively, (R)-sulfinamide (XXIV) can be obtained from the corresponding (S)-sulfinimine (XXIII) using L-selectride in an organic solvent such as THF. Such conversions are known to those skilled in the art. For example, see J. Org. Chem. 2006, 71, 6859] and/or [J. Org. Chem. 2007, 72, 626] and references therein.

Step (XXIV) → (XXV) (Step 5):

(R)-Sulfinamide (XXIV) can be converted to the corresponding (R)-amine (XXV) analogously to a number of literature procedures. For example, the reaction can be carried out using hydrogen chloride (HCl) in an aprotic organic solvent such as dioxane to obtain the corresponding HCl salt. Basic aqueous work-up provides free NH ₂ amine. For a review of sulfinimine and sulfonamide chemistry, see, e.g., Chem. Rev. 2010, 110, 3600-3740; Chem. Soc. Rev. 2009, 38, 1162-1186; Tetrahedron 2004, 60, 8003] or WO2013030138 and references thereof.

Scheme 6

Scheme 6: Alternative synthetic route for the preparation of compounds ^of formula ( _XXV ⁾ , wherein ⁵ or a protected derivative of R ⁵ .

Step (XXII) → (XXVI) (Scheme 6)

In the first step (Scheme 6), ketone derivatives of formula (XXII) (which are commercially available or described in the literature or prepared as described in Scheme 5) are purified using the corresponding chiral (S) analogously to numerous literature procedures. )-Can be converted to alcohol (XXVI). For example, enantioselective reduction can be carried out using catalysts, for example BINAP-derived catalysts, for example (R)- or (S)-RUCY-Xyl-BINAP (see WO2019/122129 page 140 or WO2013/185103 page 81) It can be carried out using catalytic hydrogenation using hydrogen gas under pressure or using the CBS-reduction (Corey-Bakshi-Shibata-Reduction) procedure. Such conversions are known to those skilled in the art and, for reference, see J. Org. Chem. 1988, 53, 2861].

Step (XXVI) → (XXVII) (Scheme 6)

The chiral (S)-alcohol (XXVI) can be converted to the corresponding (R)-azide (XXVII) analogously to a number of literature procedures. For example, the reaction can be carried out using diphenylphosphonic acid azide and a base, for example DBU, in an aprotic organic solvent such as for example toluene (see teaching on page 144 of WO2019/122129). For a review of azide chemistry, see, e.g., Chem. Rev. 1988, 88, 297] and references therein.

Step (XXVII) → (XXV) (Scheme 6)

(R)-azide (XXVII) can be converted to the corresponding (R)-amine (XXV) analogously to a number of literature procedures. For example, the reaction can be carried out using Staudinger reduction conditions using phosphine, such as triphenyl phosphine, in water with a variety of different organic solvents, such as methanol, ethanol or THF. there is. Alternatively, the azide reduction can be carried out using a catalytic hydrogenation method using a metal catalyst, for example palladium on charcoal, under a pressurized atmosphere of hydrogen (see teaching at page 144 of WO2019/122129). For a review of azide chemistry, see, e.g., Chem. Rev. 1988, 88, 297] and references therein.

Scheme 7

Scheme 7: Alternative synthetic route for the preparation ^of compounds of formula ( _XXV ⁾ , wherein ⁵ or a protected derivative of R ⁵ .

It is possible for those skilled in the art to carry out the chemical reactions described in Scheme 7, wherein the stereoisomer of (XXVIII) can be purified by various methods known to those skilled in the art, such as, for example, chiral HPLC purification. It can be separated using the separation method used. Separation of these stereoisomers can be performed on compounds of formula (XXVIII) to yield compounds having the general structure (XXV).

Scheme 8

Scheme 8: Synthetic ^route for chiral N-Boc protected amines with various functional groups for _the preparation ^of compounds of formula (XXXIII to XL ⁾ , where has the same meaning, and R ^g * and R ^h * are independently selected from -CH ₃ or -H. R ⁱ * may be selected from -CH ₃ , -CH ₂ CH ₃ or cyclopropyl.

Step (XXX) → (XXXI) (Scheme 8)

Acetyl arenes (XXX), which are commercially available or can be prepared from literature procedures, are converted to the corresponding chiral (R)-Boc amines (XXXI) according to the synthetic routes and procedures as shown in Schemes 5-7. can be converted.

Step (XXXI) → (XXXII) (Scheme 8)

The aryl iodide (XXXI) can be converted to the ester (XXXII) via literature procedures to form a new C-C bond. This transformation is known to those skilled in the art as the “Ullmann reaction” or “Negishi coupling”. For example, aryl iodide (XXXII) and fluoroalkyl bromide (XXXIa) are reacted at elevated temperature in the presence of an excess of Cu(0) powder. Alternatively, the alkyl bromide can be converted to the corresponding zinc reagent via literature procedures. For example, this transformation can be accomplished using zinc powder and an alkyl bromide (XXXIa) in an aprotic organic solvent such as DMA or THF. Coupling of the zinc reagent and aryl halide (XXXI) can be accomplished using standard palladium catalysis conditions. For example, this transformation can be achieved using tris(dibenzylideneacetone)dipalladium(0) with a suitable ligand such as SPhos in an aprotic organic solvent such as DMA or THF at elevated temperature. For example, see [Adv. Synth. Catal. 2018, 360, 1605, Chem. Commun. 2012, 48, 7738, E. J. Org. Chem. 2016, 33, 5529, J. Org. Chem 2013, 78, 8250 and/or Chem. Lett. 2015, 44, 818] and references therein.

Step (XXXII) → (XXXIII) (Scheme 8)

The ester (XXXII) can be reduced to the primary alcohol (XXXIII) using standard literature procedures. This transformation is known to the person skilled in the art and, for example, the reaction can be achieved in a protic organic solvent such as methanol or ethanol or in an aprotic organic solvent such as THF using a reducing agent such as sodium borohydride. For example, see [Adv. Synth. Catal. 2018, 360, 1605] or US2005/54658, 2005, A1, page 18 and/or Bioorg. Med. Chem. 2017, 25, 496].

Step (XXXII) → (XXXIV) (Scheme 8)

The ester (XXXII) can be converted to the tertiary alcohol (XXXIV) using standard literature procedures. This transformation is known to those skilled in the art, for example the reaction can be achieved using Grignard reagents such as methyl magnesium bromide or methyl magnesium chloride in an aprotic organic solvent such as THF. For example, see J. Am. Chem. Soc. 2020, 142, 2984] and/or [Q. Rev. Chem. Soc. 1967, 21, 259] and references therein.

Step (XXXII) → (XXXV) (Scheme 8)

The ester (XXXII) can be converted to cyclopropyl alcohol (XXXV) using standard literature procedures. This transformation is known to those skilled in the art under the name "Kulinkovich reaction", for example the reaction involves the reaction of esters in catalytic amounts in an aprotic organic solvent such as THF, diethyl ether or toluene. This can be achieved by treatment with titanium(IV) isopropoxide or titanium(IV) ethoxide and Grignard reagents such as ethyl magnesium bromide or ethyl magnesium chloride. For reference to these chemistries and training and procedures, see Org. Lett. 2013, 15, 4968, Adv. Synth. Catal. 2004, 346, 760 and/or J. Am. Chem. Soc. 2001, 123, 5777] and references therein.

Step (XXXII) → (XXXVI) (Scheme 8)

The ester (XXXII) can be hydrolyzed to the carboxylic acid (XXXVI) using standard literature procedures. This transformation is known to the person skilled in the art and, for example, the reaction can be achieved by treating the ester with lithium hydroxide in a mixture of water and THF or methanol or with sodium hydroxide in water and dioxane. See, for example, US2013/303798, 2013, A1 and/or WO2014/153667, A1 and references therein.

Step (XXXVI) → (XXXVII) (Scheme 8)

The carboxylic acid (XXXVI) can be converted to Weinreb's amide (XXXVII) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation uses N,O-dimethylhydroxylamine as a coupling partner to transform HATU, DCC, EDC*HCl, T3P, SOCl ₂ and /or can be achieved using oxalyl chloride. See, for example, EP1007514, 2006, B1, EJ Org. Chem. 2017, 25, 3584, Org. Lett. 2018, 20, 4691 and/or Adv. Synth. Catal. 2020, 362, 1106] and references therein.

Step (XXXVII) → (XXXVIII) (Scheme 8)

Weinreb's amide (XXXVII) can be converted to the ketone (XXXVIII) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished by using methyl magnesium bromide or ethyl magnesium chloride or cyclopropyl magnesium chloride in THF. For example, see Bioorg. Med. Chem. 2016, 24, 2707, Adv. Synth. Catal. 2020, 362, 1106] and/or CN104803954, 2018, B and references therein.

Step (XXXVIII) → (XXXIX) (Scheme 8)

The ketone (XXXVIII) can be converted to the secondary alcohol (XXXIX) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using sodium borohydride in a protic organic solvent such as methanol or ethanol or in an aprotic organic solvent such as THF. Alternatively, lithium aluminum hydride can be used in an aprotic organic solvent such as diethyl ether. For example, see Angew. Chem. Int. Ed. 2019, 58, 17393, J. Am. Chem. Soc. 1996, 118, 5952, and/or J. Org. Chem. 1989, 54, 661] and references therein.

Step (XXXVI) → (XL) (Scheme 8)

The carboxylic acid (XXXVI) can be converted to the amide (XL) using standard literature procedures. Such conversions are known to those skilled in the art. For example, these transformations use primary or secondary amines or ammonia (derivatives) as coupling partners, such as HATU, DCC, EDC*HCl, T3P, in organic solvents such as dichloromethane or N,N-dimethylformamide. This can be achieved using SOCl ₂ and/or oxalyl chloride. See, for example, EP1007514, 2006, B1, EJ Org. Chem. 2017, 25, 3584, Org. Lett. 2018, 20, 4691 and/or Adv. Synth. Catal. 2020, 362, 1106] and references therein.

Scheme 9

Scheme 9: Synthetic route for chiral ^N -Boc protected amines with various ^functional groups _of ^formula ( ^XLII to XLVI ⁾ , where has the same meaning as in, and R ^j * and R ^k * may be independently selected from -H or -CH ₃ .

Step (XLa) → (XLI) (Scheme 9)

The alcohol (XLa), which can be prepared according to the synthetic route and procedure as shown in Scheme 8, can be converted to triflate (XLI) using standard literature procedures. Such conversions are known to those skilled in the art. For example, the conversion can be accomplished using trifluoromethanesulfonic anhydride in combination with triethylamine or pyridine in an aprotic organic solvent such as dichloromethane. For example, see Angew. Chem. Int. Ed. 2014, 53, 6473, Adv. Synth. Catal. 2018, 360, 3667 and/or Org. Lett. 2020, 22, 6568] and references therein.

Step (XLI) → (XLII) (Scheme 9)

Triflate (XLI) can be converted to amine (XLII) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using secondary or primary amines or ammonia as nucleophiles in polar organic solvents such as acetonitrile or N,N-dimethylacetamide at elevated temperatures. For example, WO2016/49048, 2016, A1; See WO2016/44323, 2016, A1 and references therein.

Step (XLI) → (XLIII) (Scheme 9)

Triflate (XLI) can be converted to nitrile (XLIII) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using sodium cyanide as the nucleophile in a polar organic solvent such as acetonitrile, N,N-dimethylacetamide or dimethylsulfoxide at elevated temperatures. For example, US2014/194431, 2014, A1; See WO2016/44429, 2016, A1 and references therein.

Step (XLI) → (XLIV) (Scheme 9)

Triflate (XLI) can be converted to sulfone (XLIV) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using sodium methyl sulfinate as the nucleophile in a polar organic solvent such as acetonitrile, N,N-dimethylacetamide or dimethylsulfoxide at elevated temperatures. See, for example, Green Chem. 2020, 22, 322] and references therein.

Step (XLII) → (XLV) (Scheme 9)

When j* or k* = H, the amine (XLII) can be converted to the sulfonamide (XLV) using standard literature procedures. Such conversions are known to those skilled in the art. For example, the reaction can be accomplished using methanesulfonyl chloride or methanesulfonic anhydride in combination with triethylamine or potassium carbonate in an organic solvent such as dichloromethane. For example, WO2005/123747, 2005, A1, ChemMedChem 2014, 9, 614, Eur. J. Med. Chem. 2021, 211, 113053] and references therein.

Step (XLII) → (XLVI) (Scheme 9)

When j* or k* = H, the amine (XLII) can be converted to the amide (XLVI) using standard literature procedures. Such conversions are known to those skilled in the art. For example, the reaction can be accomplished using acetyl chloride or acetic anhydride in combination with triethylamine or pyridine in an organic solvent such as dichloromethane. For example, see Bioorg. Med. Chem. Lett. 2008, 18, 6429, Org. Lett. 2015, 17, 2478]; See WO2006/45498, 2006, A1 and references therein.

Scheme 10

Scheme ¹⁰ : Synthetic route for chiral N-Boc protected amines of formula ( _XLIX ^to LVI), wherein It is a protected derivative of R ⁵ or R ⁵ as in .

Step (XLVII) → (XLVIII) (Scheme 10)

Boc-protected amines (XLVII), which can be prepared according to synthetic routes and procedures as shown in Schemes 5 and 6 or are commercially available or can be prepared by literature procedures, are borylated using literature procedures. It can be converted to compound (XLVIII). This transformation is known to those skilled in the art as Hartwig-Miyaura-Borylation. For example, the reaction can be carried out with an appropriate ligand, such as 4,4'-di-tert-butyl-2,2'-dipyridine, in combination with bis(pinacolato)diborone in an aprotic organic solvent, such as THF, at elevated temperature. It can be achieved using cyclooctadiene iridium methoxide dimer ([Ir(cod)(OMe)] ₂ ) as a catalyst. For example, see J. Am. Chem. Soc. 2007, 129, 15343, J. Am. Chem. Soc. 2002, 124, 390, Science 2002, 295, 305] and references therein.

Step (XLVIII) → (XLIX) (Scheme 10)

The borylated compound (XLVIII) can be converted to the chlorinated compound (XLIX) using literature procedures. Such transformations are known to those skilled in the art and can, for example, be achieved using an excess of copper(II) chloride in a mixture of methanol and water at elevated temperatures. For example, see J. Am. Chem. Soc. 2007, 129, 15343] and references therein.

Step (XLVIII) → (L) (Scheme 10)

The borylated compound (XLVIII) can be converted to the brominated compound (L) using literature procedures. Such transformations are known to those skilled in the art and, for example, they can be achieved using an excess of copper(II) bromide in a mixture of methanol and water at elevated temperatures. For example, see J. Am. Chem. Soc. 2007, 129, 15343] and references therein.

Step (L) → (LI) (Scheme 10)

The brominated compound (L) can be converted to the formylated compound (LI) using literature procedures. Such conversions are known to those skilled in the art. For example, the transformation can be accomplished using halogen-lithium-exchange with an organolithium reagent, such as, for example, n-butyllithium, in an aprotic organic solvent, such as THF, at low temperature to produce an aryl-lithium species. , which is captured with Vilsmeier's reagent ((chloromethylene)dimethyliminium chloride). For example, see J. Organomet. Chem. 1988, 352, 1 and/or Org. Prep. Proc. Int. 2010, 42, 503] and references therein.

Step (LI) → (LII) (Scheme 10)

Formylated compounds (LI) can be converted to difluoroalkylated compounds (LII) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using DAST (N,N-diethylaminosulfur trifluoride) in an organic solvent such as dichloromethane. For example, see J. Org. Chem. 1999, 64, 7048, WO2009/121939, 2009, A1; J. Org. Chem. 1975, 40, 574] and references therein.

Step (L) → (LIII) (Scheme 10)

The brominated compound (L) can be converted to the fluorinated compound (LIII) using literature procedures. Such transformations are known to those skilled in the art, for example, by combining a palladium catalyst precursor with a hindered electron-rich phosphine ligand such as in an organic solvent such as toluene or cyclohexane and silver fluoride as a fluoride source. Adbretphos (2-(di-1-adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl) and This can be achieved by using them in combination. For example, see J. Am. Chem. Soc. 2014, 136, 3792] and references therein.

Step (L) → (LIV) (Scheme 10)

The brominated compound (L) can be converted to the hydroxylated compound (LIV) using literature procedures. These transformations are known to those skilled in the art and, for example, they can be achieved using a copper catalyst in combination with a phenanthroline ligand and a base in water as solvent. Alternatively, a phosphine ligand such as tBuBrettPshos (di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-yl) in a polar, aprotic solvent such as NMP ) Phosphine), a palladium catalyst such as palladium acetate in combination with a base and boric acid can be used. For example, see Org. Lett. 2020, 22, 8470, J. Org. Chem. 2013, 78, 5804, Green Chem. 2015, 17, 3910] and references therein.

Step (L) → (LV) (Scheme 10)

Brominated compounds (L) can be converted to aminated compounds (LV) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be achieved using a palladium catalyst such as Pd ₂ dba ₃ (tris(dibenzylideneacetone)dipalladium(0)) and a suitable phosphine ligand and ammonia in an organic solvent such as dioxane at elevated temperatures. You can. Alternatively, the copper-catalyzed conversion can be carried out using copper iodide, for example in liquid ammonia. For example, see Chem. Eur. J. 2009, 15, 4528, J. Org. Chem. 2012, 77, 7471, Chem. Soc. Rev. 2010, 39, 4130] and references therein.

Step (L) → (LVI) (Scheme 10)

The brominated compound (L) can be converted to the methylated compound (LVI) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be achieved by using a palladium catalyst such as (Pd(PPh ₃ ) ₄ ) and TMB (trimethylboroxine) as nucleophile using a base such as potassium carbonate in a mixture of water and an organic solvent such as dioxane. there is. Alternatively, a nickel-catalyzed conversion can be performed. See, for example, Tetrahedron Lett. 2000, 41, 6237, Chem. Commun. 2017, 53, 10183] and references therein.

Scheme 11

Scheme 11: Synthetic route for chiral N-Boc protected amines of formula (LIX), where X ₄ , R ⁶ , R ⁿ and R ^o have the same meaning as in formula (I) above.

Compounds of formula (XXXI) can be prepared according to literature procedures or according to the synthetic route depicted in the scheme above.

Step (XXXI) → (LVII) (Scheme 11):

Aryl iodide (XXXI) can be converted to thioether (LVII) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using a palladium catalyst such as tris(dibenzylideneacetone)-dipalladium in combination with a suitable ligand such as Xantphos and phenylmethanethiol and a base such as DIPEA in an aprotic organic solvent such as dioxane at elevated temperature. This can be achieved by using (0). Alternatively, this type of transformation has also been described using copper catalysis. For example, see Appl. Organomet. Chem. 2013, 27, 501 and Tetrahedron Lett. 2006, 47, 5781] and references therein.

Step (LVII) → (LVIII) (Scheme 11)

Thioether (LVII) can be converted to sulfonyl chloride (LVIII) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be achieved by using an oxidizing agent such as NCS or a close analog thereof, such as 1,3-dichloro-5,5-dimethylhydantoin, under acidic conditions using, for example, acetic acid and water. Sulfonyl chloride (LVIII) can be used in the next step without purification. See, for example, Tetrahedron Lett. 2010, 51, 418 and J. Org. Chem. 1996, 61, 9289] and references therein.

Step (LVIII) → (LIX) (Scheme 11)

Sulfonyl chloride (LVIII) can be converted to sulfonamide (LIX) using literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished by using the free primary or secondary amine under basic conditions using an organic base such as DIPEA or TEA in an aprotic organic solvent such as dichloromethane. For example, US2014/200277, 2014, A1; Reference [Bioorg. Med. Chem. Lett. 2006, 16, 1134, J. Med. Chem. 2010, 53, 1048] and references therein.

Scheme 12

Scheme 12: Synthetic route for deprotection of chiral amines of formula ( _LXI ^{or LXII )} , wherein ) is a protected derivative of R ⁵ or R ⁵ as in ).

The Boc-protected amine (LX), which can be prepared according to the synthetic route shown in Schemes 5-11, can be converted to the HCl salt (LXI) or the free amine (LXII) using standard literature procedures. Such conversions are known to those skilled in the art. For example, this transformation can be accomplished using a solution of hydrogen chloride in an organic solvent such as dioxane. The HCl salt (LXI) can be obtained after removal of volatile substances. Basic aqueous work-up delivers the free amine (LXII). Alternatively, trifluoroacetic acid in an organic solvent such as dichloromethane can be used for deprotection. For example, see J. Med. Chem. 2016, 59, 9150, Eur. J. Med. Chem. 2018, 145, 413, WO2012/78915, 2012, A1] and references thereof.

general method

General procedure 1:

To a solution of the substrate (1 equiv), the corresponding phosphine oxide (1 equiv) and Et ₃ N (3.5 equiv) in MeCN (0.2 M) under argon was added Pd(PPh ₃ ) ₄ (0.15 equiv) and the mixture was heated at 90°C for the indicated times. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative HPLC (basic method).

General procedure 2:

6-Bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (1 equiv) and 2,4,6-tri(propan-2-yl)benzene- in DMF (0.2M) To a solution of 1-sulfonyl chloride (1.1 equiv) was added Et ₃ N (2.5 equiv) and DMAP (0.15 equiv) and the mixture was stirred at room temperature for 1 hour. The corresponding amine (1.2 equiv) was then added and the mixture was stirred until complete conversion of the starting material was observed. The mixture was diluted with DCM and H ₂ O and the organic phase was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The desired product was obtained after purification by flash column chromatography.

General procedure 3:

To a solution of Boc-protected amine (1 equiv) in DCM (0.2M) was added TFA (10 equiv) and the mixture was stirred at room temperature until complete conversion of the starting material was observed. The mixture was diluted with toluene and concentrated under reduced pressure. The compound was used without further purification in subsequent steps.

General procedure 4:

tert-Butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl in THF (0.1M) To a solution of )ethyl]carbamate (1 equivalent) was added the corresponding Grignard reagent (3 equivalents) at room temperature. The reaction mixture was stirred at room temperature until complete conversion of the starting material was observed, quenched by slow addition of saturated aqueous NH ₄ Cl solution, and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography.

General procedure 5:

To a solution of alcohol (1 equiv) in DCM (0.2M) was added 2,6-lutidine at 0° C. and the mixture was stirred for 5 minutes. TESOTf was then added slowly and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous NaHCO ₃ solution and the organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography.

General procedure 6:

PyBOP (1.3 equiv) and 1,8-diazabicyclo(5.4.0)undec-7-ene ( 4 equiv) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed twice with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the corresponding N-arylated benzylamine.

General procedure 7:

A solution of the 1,4-lambda ⁵ -azaphosphinan-4-one derivative (A, 1.0 equiv) in dichloromethane (~1 ml/μmol A) at room temperature with N,N-diisopropylethylamine (2.5 equiv) and Acetic anhydride (1.1 equiv) was added. The mixture was stirred at room temperature typically for 3 hours (until complete reaction was indicated by analytical HPLC). The mixture was then concentrated and the residue was purified by preparative HPLC.

General procedure 8:

To a solution of the acid derivative (1.2 equiv) in DMF (0.25 M) was added HATU (1.5 equiv) and the mixture was stirred at room temperature for 5 min. The amine derivative (1 equiv) and N,N-diisopropylethylamine (2.5 equiv) were then added subsequently and the mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was purified by preparative HPLC.

General procedure 9:

To a solution of the amine derivatives (1 equiv) in DMF (0.15 M) was added the respective isocyanate (1.1 equiv) and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by preparative HPLC.

General procedure 10:

To a solution of the amine derivative (1 equiv) in DMF (0.15 M) was added N,N-diisopropylethylamine (2.5 equiv) and the respective acyl chloride (1 equiv) and the mixture was stirred at room temperature overnight. The mixture was diluted with methanol, concentrated and the residue was purified by preparative HPLC.

General procedure 11:

Triethylamine (15 equiv) in a solution of difluoroacetic acid (10 equiv) in dichloromethane (1 M), 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-amine (2.2 eq.), and 1-hydroxy-1H-benzotriazole-hydrate (2.2 eq.) were added and the mixture was stirred at room temperature for 15 minutes. Each amine (1 equiv) in dichloromethane (0.1 M) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by preparative HPLC.

Analytical LC-MS

Method 1:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquiti UPLC BEH C18 1.7 μm, 50x2.1mm; Eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; Temperature: 60℃; DAD scan: 210-400 nm.

Method 2:

Instrument: Waters Acquity UPLCMS Single Quad; Column: Acquiti UPLC BEH C18 1.7 μm, 50x2.1mm; Eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; Temperature: 60℃; DAD scan: 210-400 nm.

Method 3:

Instrument: Waters Acquity UPLCMS Single Quad; Column: Acquity UPLC BEH C18 1.7 μm, 50x2.1mm; Eluent A: water + 0.2 vol-% aqueous ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; flow rate 0.8 ml/min; Temperature: 60℃; ELSD.

Method 4:

Instrument: Waters Acquity UPLCMS Single Quad; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; Temperature: 60℃; DAD scan: 210-400 nm

Method 5:

Instrument: Waters Acquity UPLCMS Single Quad; Column: Acquiti UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; Temperature: 60℃; DAD scan: 210-400 nm

Preparative HPLC

a) Automatic purifier: acidic conditions

b) Automatic purifier: basic conditions

intermediate 1

(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol-hydrogen chloride (1/1) (5.00 g, 17.6 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. under an atmosphere of argon. 2,6-Dimethylpyridine (14 mL) was added and the suspension was stirred for 5 minutes. Triethylsilyltrifluoromethanesulfonate (16 ml, 70 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched with aqueous saturated sodium bicarbonate solution at 0°C. The organic phase was separated, dried over sodium sulfate and subsequently filtered. The solvent was evaporated to give a colorless oil (6.37 g), which was used without further purification.

LC-MS (Method 2): R _t = 1.65 min; MS (M+H) ⁺ : m/z = 362

intermediate 2

6-Chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol

A solution of 5-amino-2-chloropyridine-4-carboxylic acid (100 g, 579 mmol) and ethanimidamide hydrochloride (164 g, 1.74 mol) in 2-methoxyethanol (1.2 L) at room temperature. Sodium acetate (143 g, 1.74 mol) was added. The reaction mixture was stirred at 130°C for 48 hours. The reaction mixture was concentrated under reduced pressure to remove about 400 ml 2-methoxyethanol. The residue was poured into water and a brown solid precipitated out. The precipitate was filtered and dried under reduced pressure by oil pump to give 7-chloro-2-methylpyrido[4,3-d]pyrimidin-4-ol as a brown solid (16.6 g, 69%).

LC-MS (Method 2): R _t = 0.64 min; MS (M+H) ⁺ : m/z = 196

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.384 (16.00), 2.518 (0.89), 2.523 (0.59), 7.928 (4.21), 7.930 (4.17), 8.817 (3.76), 8.819 (3.55) ).

intermediate 3

6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol

2-Amino-5-bromopyridine-3-carboxylic acid (5.00 g, 23.0 mmol) and etanimidamide-hydrogen chloride (1/1) (7.62 g, 80.6 mmol) were dissolved in 2-methoxyethanol (60 mL). ) was dissolved in Sodium acetate (6.61 g, 80.6 mmol) was added and the mixture was heated to 150° C. for 3 days. The mixture was cooled to room temperature and poured into the ice and water mixture. The resulting solid was collected by filtration and washed with water. The solid was dried to give the title compound as a light brown solid (4.60 g, 83% yield).

LC-MS (Method 3): R _t = 0.43 min; MS (M+H) ⁺ : m/z = 240

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.392 (16.00), 2.518 (0.46), 8.554 (3.20), 8.561 (3.45), 8.986 (3.45), 8.993 (3.08), 12.659 (0.48) ).

intermediate 4

Methyl 2-chloro-6-methylpyridine-3-carboxylate

2-Chloro-6-methylpyridine-3-carboxylic acid (20.0 g, 117 mmol) and potassium carbonate (43.5 g, 315 mmol) were dissolved in dimethyl formamide (200 mL). The atmosphere was changed to argon and methyl iodide (33 ml, 520 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered and the solvent was partially evaporated. Ethyl acetate (200 mL) was added and the resulting organic phase was washed with water, then separated and dried over sodium sulfate to give the title compound as a brown oil (21 g, 97% yield).

LC-MS (Method 1): R _t = 0.90 min; MS (M+H) ⁺ : m/z = 186

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: 2.590 (10.33), 2.884 (0.62), 2.959 (0.69), 3.941 (16.00), 7.157 (1.41), 7.176 (1.48), 8.078 (2.26) ), 8.098 (2.17).

intermediate 5

Methyl 2-(tert-butylamino)-6-methylpyridine-3-carboxylate

2-(tert-butylamino)-6-methylpyridine-3-carboxylic acid (7.60 g, 36.5 mmol) and potassium carbonate (13.6 g, 98.5 mmol) were dissolved in dimethyl formamide (95 mL) at room temperature under argon. I ordered it. Iodomethane (10 ml, 160 mmol) was added dropwise and the mixture was stirred for 16 hours. The mixture was filtered and ethyl acetate was added. The resulting organic phase was washed with water and brine, then separated and dried over sodium sulfate. The compound was purified by biotage flash column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give the title compound (1.75 g, 22% yield).

LC-MS (Method 2): R _t = 1.55 min; MS (ESIpos): m/z = 223 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.450 (16.00), 2.342 (6.03), 2.518 (0.58), 3.772 (7.79), 6.443 (0.97), 6.464 (1.00), 7.940 (1.22) ), 7.960 (1.20), 8.007 (0.63).

intermediate 6

Methyl 5-bromo-2-(tert-butylamino)-6-methylpyridine-3-carboxylate

Methyl 2-(tert-butylamino)-6-methylpyridine-3-carboxylate (20.1 g, 90.4 mmol) was dissolved in acetonitrile (450 mL) and cooled to 0° C. under argon. N-Bromosuccinimide (24.1 g, 136 mmol) was added and the mixture was stirred for 1.5 hours. Saturated aqueous sodium thiosulfate solution was added and this was extracted with dichloromethane. The organic phase was dried with sodium sulfate. The compound was purified by Biotage flash column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give the title compound (12.3 g, 45% yield).

LC-MS (Method 2): R _t = 1.74 min; MS (ESIpos): m/z = 301 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.440 (16.00), 2.468 (7.06), 2.518 (0.75), 2.523 (0.55), 3.324 (0.46), 3.796 (8.22), 7.957 (0.65) ), 8.086 (2.37).

intermediate 7

Trifluoroacetic acid-methyl 2-amino-5-bromo-6-methylpyridine-3-carboxylate (1/1)

To methyl 5-bromo-2-(tert-butylamino)-6-methylpyridine-3-carboxylate (12.3 g, 40.8 mmol) was added trifluoroacetic acid (120 ml, 1.5 mol), and the mixture was It was stirred at 120°C for 45 minutes using a microwave. Toluene was added and the solvent was evaporated to give a crude solid (15.1 g, 103% yield), which was used without further purification.

LC-MS (Method 2): R _t = 1.10 min; MS (ESIpos): m/z = 245 [M+H] ⁺

intermediate 8

2-Amino-5-bromo-6-methylpyridine-3-carboxylic acid

Trifluoroacetic acid-methyl 2-amino-5-bromo-6-methylpyridine-3-carboxylate (1/1) (15.1 g, 92% purity, 38.7 mmol) was purified in methanol (180 mL) under argon at room temperature. ) was dissolved in Sodium hydroxide solution (150 ml, 5 wt%, 190 mmol) was added and the resulting suspension was stirred for 16 hours. The methanol was evaporated and aqueous hydrochloric acid (2.5 M) was added until a solid was formed. Acetic acid was added until pH 4 was reached. The solid was filtered, washed with water and ether and dried at 70° C. under vacuum to give the title compound (7.5 g, 84% yield).

LC-MS (Method 1): R _t = 0.67 min; MS (ESIpos): m/z = 231 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.907 (0.20), 2.251 (0.08), 2.412 (16.00), 2.518 (1.53), 2.523 (1.06), 2.570 (0.09), 3.324 (0.67) ), 4.399 (0.08), 7.291 (0.14), 8.042 (6.41).

intermediate 9

6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol

Substrate 2-amino-5-bromo-6-methylpyridine-3-carboxylic acid (3.50 g, 15.1 mmol), acetamidine hydrochloride (6.44 g, 68.2 mmol) in 2-methoxyethanol (30 mL) and sodium acetate (1.24 g, 15.1 mmol) was heated at 135° C. for 4 days. Additional 2-methoxyethanol (30 ml) and acetamidine hydrochloride (1.43 g, 15.1 mmol) and sodium acetate (1.24 g, 15.1 mmol) were added and heated at 140° C. for a further 2 days. Additional 2-methoxyethanol (20 mL) and acetamidine hydrochloride (2.86 g, 30.3 mmol) and sodium acetate (2.49 g, 30.3 mmol) were added and heated at 140° C. for another 1 day. The reaction mixture was poured into ice water, and the resulting suspension was filtered. The residue was washed with water and dried at 65° C. under reduced pressure over 3 days to give the title compound as a light brown solid (2.95 g, 77% yield).

LC-MS (Method 1): R _t = 0.70 min; MS (ESIneg): m/z = 252 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.08), 1.752 (0.07), 1.899 (0.37), 2.208 (0.08), 2.318 (0.14), 2.322 (0.31), 2.327 (0.42) ), 2.331 (0.32), 2.336 (0.17), 2.371 (16.00), 2.518 (4.96), 2.522 (3.84), 2.659 (0.25), 2.665 (0.44), 2.669 (0.72), 2.678 (13.68), 2. 838 (0.08 ), 3.239 (0.41), 8.479 (4.79), 12.596 (0.05).

intermediate 10

Methyl 2-acetamido-5-bromo-6-(trifluoromethyl)pyridine-3-carboxylate

DMAP (3.76 mg) in a solution of methyl 2-amino-5-bromo-6-(trifluoromethyl)pyridine-3-carboxylate (920 mg, 3.08 mmol) in Ac ₂ O (61 ml, 650 mmol) , 30.8 μmol) was added, and the mixture was stirred at 100°C for 2 days. Toluene was then added at room temperature and the mixture was concentrated under reduced pressure. The crude product was dried under vacuum and used in the next step without further purification (1.05 g, 100% yield).

LC-MS (Method 2): R _t = 1.12 min; MS (ESIpos): m/z = 341 [M+H] ⁺

Intermediate 11

6-Bromo-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-ol

Methyl 2-acetamido-5-bromo-6-(trifluoromethyl)pyridine-3-carboxylate (1.05 g, 3.08 mmol) in aqueous NH ₄ OH-solution (28-30%, 93 ml) A solution of (1.05 g, 3.08 mmol) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with H ₂ O and extracted with EtOAc. The combined organic portion was obtained. The phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The title compound (630 mg, 66% yield) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 1): R _t = 0.93 min; MS (ESIpos): m/z = 308 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.810 (0.52), 1.850 (0.73), 1.987 (0.66), 2.422 (16.00), 2.518 (0.95), 2.523 (0.66), 8.827 (2.58) ), 12.878 (0.47).

intermediate 12

6-Bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[2,3 -d]pyrimidin-4-amine

6-Bromo-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-ol (250 mg, 812 μmol), (1R)- in DMF (6.3 mL) In a solution of 1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (594 mg, 2.92 mmol) and PyBOP (1.65 g, 3.16 mmol) was added 1,8-diazabicyclo (5.4 .0)Undec-7-ene (1.5 ml, 9.7 mmol) was added and the reaction mixture was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic portion was obtained. The phases were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The title compound (258 mg, 64% yield) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.51 min; MS (ESIpos): m/z = 495 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.85), 1.172 (1.60), 1.189 (0.74), 1.562 (4.55), 1.579 (4.46), 1.987 (3.19), 2.323 (0.52) ), 2.327 (0.73), 2.331 (0.51), 2.406 (16.00), 2.518 (2.67), 2.523 (1.91), 2.605 (5.08), 2.665 (0.53), 2.669 (0.74), 2.673 (0.50), 4.0 17 (0.63 ), 4.035 (0.64), 5.687 (0.66), 5.705 (1.02), 5.722 (0.64), 5.759 (0.56), 7.352 (0.57), 7.372 (1.28), 7.391 (0.78), 7.558 (1.39), 7.57 6 (1.11 ), 7.754 (1.22), 7.773 (1.09), 9.188 (1.03), 9.206 (1.00), 9.480 (3.55).

Intermediate 13

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]- 2-methylpyrido[3,4-d]pyrimidin-4-amine

6-Chlor-2-methylpyrido[3,4-d]pyrimidin-4-ol (2.87 g, 14.7 mmol) was suspended in N,N-dimethylformamide (29 mL). 2,4,6-Triisopropylbenzenesulfonylchloride (4.89 g, 16.2 mmol) was added followed by triethylamine (7.2 ml, 51 mmol) at room temperature. The mixture was stirred for 1 hour. (1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethanamine (6.37 g, 17.6 mmol) was added. And the resulting mixture was stirred at room temperature for 16 hours. The solvent was partially evaporated and the residue was redissolved in dichloromethane and water. The organic phase was washed with water (twice) and brine. The organic phase was dried through hydrophobic filtration. The solvent was evaporated and the compound was purified via flash column chromatography on Biotage using silica gel and hexane and ethyl acetate as eluents to give the title compound (6.00 g, 97% purity, 74% yield).

LC-MS (Method 2): R _t = 1.77 min; MS (ESIneg): m/z = 537 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.382 (1.24), 0.385 (1.24), 0.404 (5.28), 0.424 (7.14), 0.442 (2.59), 0.662 (7.85), 0.672 (0.86) ), 0.681 (16.00), 0.689 (0.81), 0.701 (5.46), 1.233 (0.41), 1.321 (4.11), 1.329 (4.29), 1.577 (3.02), 1.594 (3.00), 2.332 (1.09), 2.3 36 (0.51 ), 2.382 (10.57), 2.518 (7.29), 2.522 (4.80), 2.673 (1.12), 2.678 (0.48), 5.751 (0.46), 5.768 (0.74), 5.786 (0.46), 7.204 (0.43), 7.2 23 (1.04 ), 7.242 (0.74), 7.281 (0.48), 7.297 (0.63), 7.622 (0.63), 8.548 (2.57), 8.550 (2.59), 8.835 (2.82), 8.847 (0.79), 8.865 (0.76).

Intermediate 14

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl] -2,8-dimethylpyrido[3,4-d]pyrimidin-4-amine

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl] -2-Methylpyrido[3,4-d]pyrimidin-4-amine (1.35 g, 2.50 mmol) was dissolved in dimethylsulfoxide (20 mL) in a round flask. 1,8-Diazabicyclo(5.4.0)undec-7-ene (750 μl, 5.0 mmol) was added followed by nitromethane (680 μl, 13 mmol). The mixture was stirred at room temperature for 16 hours. Ethyl acetate and water were added, the phases were separated and the organic phase was dried via hydrophobic filtration. The compound was purified via Biotage flash column chromatography on silica gel using hexane and ethyl acetate as eluents to give the title compound (1.00 g, 72% yield).

LC-MS (Method 2): R _t = 1.91 min; MS (ESIpos): m/z = 553 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.365 (1.71), 0.384 (6.14), 0.404 (7.75), 0.423 (3.26), 0.651 (8.53), 0.670 (16.00), 0.691 (6.74) ), 1.293 (5.37), 1.305 (5.88), 1.565 (3.47), 1.582 (3.58), 2.361 (9.67), 2.680 (8.64), 5.720 (0.61), 5.737 (0.95), 5.748 (1.31), 5.75 5 (0.69 ), 7.165 (0.54), 7.185 (1.29), 7.204 (0.93), 7.246 (0.70), 7.263 (0.95), 7.278 (0.47), 7.567 (0.54), 7.584 (0.92), 7.599 (0.53), 8.31 9 (2.76 ), 8.687 (1.06), 8.704 (1.05).

intermediate 15

6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol (2.00 g, 8.33 mmol), (1R)-1-[2-methyl-3- in DMF (60 mL) To a solution of (trifluoromethyl)phenyl]ethan-1-amine (2.03 g, 10.0 mmol) and PyBOP (5.64 g, 10.8 mmol) was added DBU (5.0 ml, 33 mmol) and the reaction mixture was incubated at room temperature overnight. It was stirred. The mixture was concentrated under reduced pressure and the title compound (1.37 g, 39% yield) was obtained after purification by silica chromatography and subsequent recrystallization from CH ₂ Cl ₂ /MTBE.

LC-MS (Method 2): R _t = 1.32 min; MS (ESIpos): m/z = 425 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.12), 1.171 (2.50), 1.189 (1.28), 1.470 (1.34), 1.487 (1.36), 1.551 (5.16), 1.569 (5.23) ), 1.986 (4.69), 2.396 (16.00), 2.448 (1.37), 2.518 (3.22), 2.522 (2.12), 2.606 (5.94), 2.673 (0.56), 4.016 (0.99), 4.034 (0.97), 5.6 95 (0.73 ), 5.713 (1.12), 5.730 (0.71), 7.350 (0.66), 7.369 (1.45), 7.389 (0.85), 7.551 (1.60), 7.569 (1.29), 7.756 (1.42), 7.775 (1.29), 9.00 3 (3.41 ), 9.009 (3.59), 9.198 (2.97), 9.204 (2.69).

intermediate 16

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl ]-2-methylpyrido[2,3-d]pyrimidin-4-amine

6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol (3.89 g, 16.2 mmol), (1R)-1-(3-{1,1) in DMF (120 mL) -difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (16.1 g, 17.8 mmol) and PyBOP (10.0 g, 17.8 mmol) DBU (9.7 ml, 64.8 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with H ₂ O (2x) and brine and dried over Na ₂ SO ₄ . The mixture was filtered, concentrated under reduced pressure and the title compound (5.55 g, 59%) was obtained after purification by silica chromatography (basic phase, hexane/EtOAc).

LC-MS (Method 2): R _t = 1.72 min; MS (ESIpos): m/z = 583 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.384 (1.14), 0.387 (1.21), 0.405 (5.21), 0.417 (0.57), 0.425 (7.62), 0.434 (0.56), 0.444 (2.69) ), 0.663 (7.57), 0.674 (0.88), 0.682 (16.00), 0.691 (1.14), 0.703 (5.64), 1.323 (3.86), 1.332 (4.28), 1.566 (2.95), 1.584 (2.98), 2.3 67 (11.84 ), 2.518 (5.24), 2.523 (3.80), 3.321 (0.48), 5.753 (0.44), 5.770 (0.71), 5.788 (0.46), 7.199 (0.41), 7.218 (1.02), 7.238 (0.73), 7.27 2 (0.40 ), 7.276 (0.50), 7.293 (0.64), 7.622 (0.62), 8.790 (0.76), 8.808 (0.74), 8.991 (2.74), 8.998 (2.85), 9.199 (2.02), 9.205 (1.92).

Intermediate 17

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-2-methylpropan-2-ol

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}- in dichloromethane (15 mL) 2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (1.00 g, 1.71 mmol) and triethylsilane (27 μl, 170 μmol) Roacetic acid (2.0 ml, 26 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature overnight. Toluene was then added and volatiles were removed under reduced pressure. The title compound (815 mg, 100% yield) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.15 min; MS (ESIpos): m/z = 469 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.58), 1.171 (3.21), 1.189 (1.98), 1.202 (6.11), 1.226 (6.29), 1.563 (4.70), 1.580 (4.70) ), 1.986 (5.14), 2.326 (1.01), 2.332 (0.75), 2.368 (16.00), 2.518 (4.79), 2.522 (3.16), 2.669 (1.01), 2.673 (0.75), 4.017 (1.19), 4.0 34 (1.19 ), 5.338 (2.24), 5.731 (0.75), 5.748 (1.14), 5.766 (0.70), 7.197 (0.70), 7.216 (1.67), 7.235 (1.05), 7.299 (0.66), 7.303 (0.75), 7.32 1 (1.05 ), 7.336 (0.53), 7.340 (0.44), 7.588 (0.62), 7.604 (1.05), 7.620 (0.53), 8.803 (1.23), 8.821 (1.19), 8.995 (3.69), 9.002 (3.65), 9.19 6 (3.16 ), 9.202 (2.99).

intermediate 18

6-Bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidine-4 -Amine

6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol (1.50 g, 5.90 mmol), (1R)-1-[2-methyl- 1,8-Diazabicyclo(5.4.0)undece-7 in a solution of 3-(trifluoromethyl)phenyl]ethane-1-amine (1.44 g, 7.08 mmol) and PyBOP (3.99 g, 7.67 mmol) -N (3.5 ml, 24 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water was added and the aqueous phase was extracted with dichloromethane. The combined organic portion was obtained. The phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound (1.45 g, 56% yield) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.37 min; MS (ESIpos): m/z = 441 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (3.17), 1.171 (6.28), 1.189 (3.01), 1.560 (5.52), 1.578 (5.54), 1.986 (12.05), 2.414 (14.52) ), 2.518 (1.28), 2.523 (0.82), 2.596 (6.89), 2.706 (16.00), 3.998 (0.85), 4.016 (2.49), 4.034 (2.51), 4.052 (0.83), 5.720 (0.79), 5.7 38 (1.19 ), 5.758 (1.89), 7.363 (0.74), 7.383 (1.65), 7.402 (0.97), 7.562 (1.81), 7.580 (1.46), 7.758 (1.63), 7.777 (1.46), 9.192 (4.67), 9.31 5 (0.41 ).

Intermediate 19

6-Bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3-d]pyrimidine- 4-amine

6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol (500 mg, 1.97 mmol), (1R)-1 in N,N-dimethylformamide (17 mL) -[3-(difluoromethyl)-2-fluorophenyl]ethane-1-amine 1,8 in a solution of hydrogen chloride (1/1) (511 mg, 2.26 mmol) and PyBOP (1.33 g, 2.56 mmol) -Diazabicyclo(5.4.0)undec-7-ene (1.2 ml, 7.9 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water, ethyl acetate and organic matter were added. The phases were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound (625 mg, 75% yield) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.24 min; MS (ESIpos): m/z = 427 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.83), 1.172 (3.84), 1.190 (1.87), 1.579 (4.53), 1.597 (4.51), 1.988 (6.18), 2.337 (0.44) ), 2.364 (16.00), 2.518 (4.31), 2.523 (2.92), 2.673 (0.93), 2.678 (0.58), 2.691 (14.37), 3.999 (0.46), 4.017 (1.37), 4.035 (1.31), 4. 053 (0.42 ), 5.732 (0.68), 5.750 (1.03), 5.767 (0.68), 7.101 (1.05), 7.237 (2.17), 7.275 (0.72), 7.294 (1.57), 7.313 (0.93), 7.373 (0.91), 7.49 4 (0.54 ), 7.511 (0.91), 7.529 (0.44), 7.659 (0.52), 7.678 (0.89), 7.695 (0.46), 8.763 (0.48), 8.778 (0.48), 9.144 (4.57).

intermediate 20

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl ]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine

6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol (120 mg, 472 μmol), (1R)-1-(3-{1) in DMF (4.0 mL) ,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (196 mg, 543 μmol) and PyBOP (320 mg, 614 μmol) ) was added to the solution of DBU (280 μl, 1.9 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with H ₂ O and EtOAc and the organic phase was washed with H ₂ O (2x) and brine and dried over Na ₂ SO ₄ . The mixture was filtered, concentrated under reduced pressure and the title compound (122 mg, 43%) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.74 min; MS (ESIpos): m/z = 567 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.388 (1.44), 0.389 (1.44), 0.409 (5.84), 0.429 (7.47), 0.448 (2.94), 0.664 (8.29), 0.683 (16.00) ), 0.704 (5.90), 1.325 (5.42), 1.331 (5.67), 1.556 (3.40), 1.574 (3.39), 1.987 (0.45), 2.343 (10.70), 2.522 (1.42), 2.684 (9.83), 5.7 45 (0.54 ), 5.763 (0.84), 5.781 (0.53), 7.195 (0.49), 7.214 (1.23), 7.233 (0.88), 7.271 (0.61), 7.287 (0.81), 7.591 (0.47), 7.608 (0.79), 7.62 4 (0.43 ), 8.711 (0.95), 8.729 (0.91), 9.149 (3.42).

intermediate 21

1-(3-{(1R)-1-[(6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl )-1,1-difluoro-2-methylpropan-2-ol

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl in CH ₂ Cl ₂ (5.9 mL) }-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (400 mg, 669 μmol) and triethylsilane (11 μl, 67 μmol) TFA (770 μl, 10 mmol) was added dropwise to the solution at room temperature. The mixture was stirred at room temperature overnight. Toluene was then added and volatiles were removed under reduced pressure. The title compound (320 mg, 99%) was obtained after purification by silica chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.19 min; MS (ESIpos): m/z = 485 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.20), 1.172 (4.73), 1.190 (2.99), 1.202 (6.97), 1.217 (6.94), 1.625 (4.90), 1.643 (4.87) ), 1.907 (0.47), 1.987 (6.92), 2.327 (0.94), 2.331 (0.65), 2.518 (4.10), 2.523 (2.67), 2.669 (0.98), 2.673 (0.65), 2.761 (16.00), 3.9 99 (0.58 ), 4.017 (1.68), 4.035 (1.67), 4.053 (0.53), 5.361 (0.81), 5.838 (0.76), 5.856 (1.17), 5.874 (0.73), 7.261 (0.76), 7.280 (1.82), 7.29 9 (1.17 ), 7.358 (0.72), 7.362 (0.81), 7.379 (1.15), 7.395 (0.55), 7.399 (0.48), 7.654 (0.64), 7.671 (1.11), 7.686 (0.58), 9.321 (4.32).

intermediate 22

6-chloro-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidin-4-amine

6-chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol (6.00 g, 30.7 mmol) and 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl Chloride (10.2 g, 33.7 mmol) was dissolved in N,N-dimethylformamide (60 mL). Triethylamine (11 ml) was added, followed by 4-(dimethylamino)pyridine (562 mg, 4.60 mmol). The mixture was stirred at room temperature for 1 hour. (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (7.48 g, 36.8 mmol) was then added and the mixture was stirred for 16 hours. Dichloromethane and water were added, the organic phase was washed with water and brine, dried over sodium sulfate and the solvent was evaporated. The compound was purified by Biotage flash column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give the title compound (9.98 g, 85% yield).

LC-MS (Method 2): R _t = 1.39 min; MS (ESIneg): m/z = 379 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.44), 1.171 (0.97), 1.189 (0.51), 1.553 (4.57), 1.570 (4.57), 1.986 (1.77), 2.386 (16.00) ), 2.518 (1.28), 2.523 (0.86), 2.609 (4.97), 5.668 (0.57), 5.685 (0.88), 5.703 (0.57), 7.343 (0.55), 7.362 (1.24), 7.382 (0.72), 7.54 4 (1.33 ), 7.561 (1.07), 7.751 (1.18), 7.770 (1.07), 8.525 (3.73), 8.527 (3.64), 8.818 (3.98), 8.820 (3.79), 8.967 (0.86), 8.984 (0.84).

intermediate 23

6-chloro-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[3,4-d]pyrimidin-4-amine

6-Chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol (433 mg, 2.22 mmol) and 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl Chloride (738 mg, 2.44 mmol) was dissolved in N,N-dimethylformamide (4.3 mL). Triethylamine (770 μl) was added, followed by 4-(dimethylamino)pyridine (40.6 mg, 332 μmol). The mixture was stirred at room temperature for 1 hour. (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethane-1-amine-hydrogen chloride (1/1) (600 mg, 2.66 mmol) was added and the mixture was stirred for 16 hours. It was stirred. Dichloromethane and water were added, the organic phase was washed with water and brine, dried over sodium sulfate and the solvent was evaporated. The compound was purified by Biotage flash column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give the title compound (0.57 g, 70% yield).

LC-MS (Method 2): R _t = 1.25 min; MS (ESIpos): m/z = 367 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (3.83), 1.172 (7.69), 1.190 (3.67), 1.598 (4.72), 1.615 (4.75), 1.988 (12.40), 2.397 (16.00) ), 2.518 (1.81), 2.523 (1.25), 4.000 (0.93), 4.017 (2.87), 4.035 (2.88), 4.053 (0.94), 5.732 (0.71), 5.750 (1.11), 5.759 (2.44), 5.76 8 (0.70 ), 7.102 (1.04), 7.238 (2.18), 7.280 (0.73), 7.299 (1.60), 7.318 (0.92), 7.373 (0.94), 7.499 (0.54), 7.516 (0.92), 7.534 (0.44), 7.67 0 (0.50 ), 7.687 (0.92), 7.706 (0.45), 8.537 (3.84), 8.539 (3.82), 8.841 (4.23), 8.867 (1.04), 8.885 (1.01).

intermediate 24

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-6-( dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl} in acetonitrile (1.3 ml) under argon. -2-fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (100 mg, 185 μmol), dimethyl-lambda ⁵ -phosphanone (14.5 mg, 185 μmol) and tetrakis(triphenylphosphine)palladium(0) (42.9 mg, 37.1 μmol; CAS-RN:[ 14221-01-3]) was added and the mixture was heated at 100° C. for 2 days. The mixture was filtered, concentrated and the crude product was used directly in the next step.

LC-MS (Method 2): Rt = 1.59 min; MS (ESIpos): m/z = 581.6 [M+1]+

intermediate 25

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-6-( dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-amine

Following General Procedure 1, 6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2- Fluorophenyl)ethyl]-2,8-dimethylpyrido[3,4-d]pyrimidin-4-amine (83.0 mg, 150 μmol) was reacted with dimethyl-lambda ⁵ -phosphanone ( 11.7 mg, 150 μmol), tetrakis(triphenylphosphine)palladium(0) (27.5 mg, 30.0 μmol, 0.20 equivalent) and triethylamine (73 μl, 530 μmol) at 90°C for 20 hours. The mixture was cooled to room temperature, ethyl acetate and water were added, the phases were separated and the organic phase was dried via hydrophobic filtration. The solvent was evaporated to give a light yellow oil, which was used as the crude mixture without further purification.

LC-MS (Method 2): R _t = 1.78 min; MS (ESIpos): m/z = 595 [M+H] ⁺

intermediate 26

(S,E)-N-Ethylidene-2-methylpropane-2-sulfinamide

The reaction was carried out in parallel as two batches: (S)-2-methylpropane-2-sulfinamide (200 g, 1.65 mol) in DCM (1.5 L), acetaldehyde (500 ml, 5 M in THF) and A mixture of MgSO4 (750 g, 6.23 mol) was stirred at 20° C. for 28 hours. The two reaction mixtures were combined and filtered. The filter cake was washed with DCM (1000 ml x 2). The combined filtrates were concentrated under vacuum. The residue was purified by chromatography on silica gel (3% EA in PE) to give (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (410 g, 84.37% yield) as a pale yellow oil. It was obtained as.

^1H NMR (CDCl3 400MHz) 8.07 (q, 1H), 2.23 (d, 2H), 1.16 (s, 9H)

intermediate 27

(S)-N-((R)-1-(2-fluoro-3-iodophenyl)ethyl)-2-methylpropane-2-sulfinamide

The reaction was carried out in parallel as four batches: solution n-BuLi (320 ml, 2.5 M in hexane) was added with N-isopropylpropan-2-amine (120 ml, 849.10 mmol) in THF (300 ml) at -20 After adding dropwise at ℃, it was stirred for 1 hour and cooled to -60℃. A solution of 1-fluoro-2-iodo-benzene (180 g, 810.82 mmol) in THF (300 ml) was added dropwise to the reaction. After stirring for 2 hours, a solution of (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (100 g, 679.17 mmol) in THF (300 ml) was added dropwise at -60°C under N2. did. The mixture was warmed to 20° C. and stirred for 16 hours. Each reaction solution was poured into saturated aqueous NH4Cl (3 L) and extracted with MTBE (800 ml x 3). The combined organic solutions were washed with brine (500 ml), dried over Na2SO4, filtered and concentrated in vacuo. Four batches were combined and purified for three times by chromatography on silica gel (PE:EA = 10:1 to 1:2) to give the desired product (94 g, 254.58 mmol) as a light brown oil (containing ~0.04 equivalent isomers). It was obtained as.

^1H NMR (CDCl3 400MHz) 7.63-7.67 (m, 1H), 7.30-7.33 (m, 1H), 6.86-6.91 (m, 1H), 4.81-4.86 (m, 1H), 3.41 (d, 1H), 1.57 (d, 2H), 1.23 (s, 9H)

intermediate 28

(R)-1-(2-fluoro-3-iodophenyl)ethanamine hydrochloride

(S)-N-[(1R)-1-(2-fluoro-3-iodo-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (94 g, To a solution of 254.58 mmol), HCl/dioxane (4 M, 140 ml) was added at 20° C., and the reaction was stirred for 2 hours. TLC (PE:EA = 1:1) showed the reaction was complete. MTBE (300 ml) was added to the mixture and filtered. The filter cake was washed with MTBE (50 ml Obtained as a solid.

¹ H NMR (DMSO-d6 400 MHz) 8.70 (s, 1H), 7.84-7.88 (m, 1H), 7.66-7.69 (m, 1H), 7.08-7.12 (m, 1H), 4.58-4.61 (m, 1H), 1.52 (d, 3H)

intermediate 29

(R)-tert-butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate

To a solution of (R)-1-(2-fluoro-3-iodophenyl)ethanamine hydrochloride (67 g, 222.20 mmol) in H2O (300 ml) and THF (300 ml) was added NaHCO3 (70 g, 833.27 mmol) was added, followed by Boc2O (52 g, 238.26 mmol), and the reaction was stirred at 25°C for 1 hour. TLC (DCM: MeOH = 10: 1) showed the reaction was complete. The mixture was extracted with MTBE (300 ml x 3). The combined organic solutions were washed with brine (300 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with PE (100 ml) and filtered. The filter cake was dried under vacuum to yield (R)-tert-butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate (75 g, 92.43% yield) as a pale yellow solid.

¹ H NMR (MeOD 400 MHz) 7.64-7.68 (m, 1H), 7.31-7.35 (m, 1H), 6.90-6.95 (m, 1H), 4.86-4.94 (m, 1H), 1.51 (d, 3H) , 1.25 (s, 9H)

intermediate 30

(R)-Ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate

A mixture of ethyl 2-bromo-2,2-difluoro-acetate (40 ml, 311.36 mmol) and Cu (40 g, 629.43 mmol) in DMSO (300 ml) was stirred at 20° C. for 1 h. (R)-tert-butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate (75 g, 205.38 mmol) was added, and the reaction was heated and stirred at 80°C for 5 hours. TLC (PE: EA = 3: 1) showed the reaction was complete. The reaction was cooled and extracted directly with MTBE (500 ml x 4). The combined MTBE solutions were washed with saturated NH4Cl (300 ml x 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EA = 20:1 to 5:1) to give (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl )-2-Fluorophenyl)-2,2-difluoroacetate (45 g, 60.64% yield) was obtained as a light yellow oil.

^1H NMR (CDCl3 400 MHz) 7.52-7.56 (m, 1H), 7.44-7.48 (m, 1H), 7.20-7.25 (m, 1H), 4.97 (br s, 3H), 4.33-4.39 (m, 2H) ), 1.51 (d, 3H), 1.19-1.45 (m, 12H).

Intermediate 31

tert-Butyl (R)-(1-(3-(1,1-difluoro-2-(methoxy(methyl)amino)-2-oxoethyl)-2-fluorophenyl)-ethyl)carba mate

Ethyl (3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-2-fluorophenyl)(difluoro) in tetrahydrofuran (330 ml) under argon at -15°C. To a solution of acetate (16.4 g, 45.4 mmol) and N-methoxymethanamine hydrogen chloride (1/1) (6.64 g, 68.1 mmol) was added N,N-diisopropylethylamine (12 ml) and the solution was Stirred for 5 minutes. 2-Propylmagnesium chloride (2M in THF, 110 ml, 2.0 M, 230 mmol) was then added dropwise and the resulting solution was stirred at -15°C to -10°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, filter-dried and concentrated. The crude product was purified by flash column chromatography to give the title compound (13.8 g, 81% yield).

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.54), 1.172 (5.05), 1.190 (2.60), 1.274 (5.68), 1.291 (5.71), 1.342 (16.00), 1.987 (8.09) ), 2.327 (0.45), 2.518 (1.66), 2.523 (1.17), 2.669 (0.46), 3.198 (8.59), 3.223 (1.92), 3.999 (0.58), 4.017 (1.73), 4.035 (1.69), 4.05 3 (0.53 ), 4.843 (0.49), 4.862 (0.68), 4.880 (0.45), 7.333 (0.89), 7.353 (2.11), 7.372 (1.30), 7.483 (0.91), 7.500 (1.41), 7.516 (0.65), 7.54 5 (0.77 ), 7.562 (1.35), 7.584 (1.27), 7.605 (0.76).

intermediate 32

6-Bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol

5-Amino-2-bromoisonicotinic acid (CAS 1242336-80-6, 50 g, 230 mmol) and ethanimidamide hydrochloride (1:1) (65 g, Sodium acetate (57 g, 691 mmol) was added to the solution and stirred at 160°C for 48 hours. The mixture was cooled to room temperature, diluted with water and stirred for 1 hour. The resulting precipitate was filtered and dried under vacuum to give the title compound (44 g, 76% yield).

LC-MS (Method 2): Rt = 0.48 min; MS (ESIpos): m/z = 240 [M+H]+amino

Intermediate 33

2-Amino-5-bromo-6-methoxypyridine-3-carboxamide

To a solution of 2-amino-6-methoxypyridine-3-carboxamide (19.0 g, 114 mmol) in DMF (160 ml) was added NBS (22.3 g, 125 mmol) and the reaction mixture was incubated for 2 hours at 25°C. Stirred for an hour. The mixture was concentrated, the residue was triturated with water (200 ml) and the resulting solid was dried under reduced pressure to give the title compound (20.0 g, 64% yield) as a brown solid, which was used without further purification.

Intermediate 34

6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol

2-Amino-5-bromo-6-methoxypyridine-3-carboxamide (Intermediate 33, 52 g, 90% purity, 211 mmol) and triethyl orthoacetate ( 165 g, 1.02 mol) of the solution was stirred at 120°C for 2 hours. The resulting suspension was filtered, and the precipitate was recrystallized from 2-propanol to obtain 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol as a brown solid (27.8 g). , 96% purity, 49% yield).

LC-MS (Method 2): R _t = 0.54 min; MS (ESIpos): m/z = 272 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.55 (br s, 1 H), 8.45 (s, 1 H), 4.00 - 4.07 (m, 3 H), 2.52 - 2.55 (m, 1 H) , 2.36 (s, 3 H)

intermediate 35

6-Bromo-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d] Pyrimidin-4-amine

According to General Procedure 6, 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 34, 900 mg, 3.33 mmol) and (1R)-1 Starting from -[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine hydrogen chloride (1/1) (879 mg, 3.67 mmol), the title compound was obtained (1.22 g, 80% yield) ).

LC-MS (Method 2): R _t = 1.40 min; MS (ESIpos): m/z = 455 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.84 Hz, 3 H) 2.33 (s, 3 H) 2.60 (s, 3 H) 4.00 (s, 3 H) 5.57 - 5.74 ( m, 1 H) 7.27 - 7.40 (m, 1 H) 7.45 - 7.60 (m, 1 H) 7.71 - 7.80 (m, 1 H) 8.58 - 8.70 (m, 1 H) 9.12 (s, 1 H).

Intermediate 36

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxopropyl)-2-fluorophenyl]ethyl}carbamate

According to General Procedure 4: tert-butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl} in THF (120 ml) -2-Fluorophenyl)ethyl]carbamate (4.00 g, 10.6 mmol) and bromido(methyl)magnesium (32 ml, 1.0 M, 32 mmol) were reacted at -10°C to 0°C for 1.5 hours. The title compound (3.63 g, quantitative) was obtained after aqueous work-up and used in the next step without further purification.

LC-MS (Method 2): R _t = 1.29 min; MS (ESIpos): m/z = 332 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.87), 1.172 (0.63), 1.190 (0.40), 1.272 (6.20), 1.289 (6.20), 1.353 (16.00), 2.443 (8.06) ), 2.518 (1.59), 2.523 (1.09), 4.851 (0.45), 4.869 (0.62), 4.887 (0.42), 5.759 (0.88), 7.356 (0.72), 7.376 (1.65), 7.395 (1.01), 7.53 3 (0.89 ), 7.550 (1.41), 7.566 (0.73), 7.569 (0.74), 7.596 (1.11), 7.614 (1.59), 7.633 (0.67).

Intermediate 37

tert-Butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]carbamate

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxopropyl)-2-fluorophenyl]ethyl}carbamate (3.63 g, 97%) in EtOH (42 ml) % purity, 10.6 mmol) NaBH ₄ was added little by little at 0°C. The mixture was stirred at room temperature for 2 hours and then poured into saturated aqueous NH ₄ Cl solution at 0°C. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by flash column chromatography gave a mixture of diastereomers (3.32 g, 94% yield), which was separated by chiral HPLC.

For purification - method: SFC

Instrument: Sepiatec: SFC100 for purification; Column: Chiralpak IG 5 μ 250x30mm; Eluent A: CO2; Eluent B: methanol; Isocratic: 10%B; Flow rate: 100 ml/min; Temperature: 40℃; BPR: 150bar; UV: 210 nm

LC-MS (Method 2): R _t = 1.16 min; MS (ESIpos): m/z = 351 [M+NH ₄ ⁺ ] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.135 (3.55), 1.147 (3.69), 1.171 (1.70), 1.189 (1.04), 1.277 (4.65), 1.281 (4.31), 1.294 (4.89) ), 1.361 (16.00), 1.986 (1.18), 4.126 (0.44), 4.147 (0.63), 4.164 (0.64), 4.183 (0.45), 4.909 (0.69), 5.555 (1.07), 5.571 (1.11), 5.5 88 (0.80 ), 5.604 (0.72), 7.247 (0.77), 7.266 (1.87), 7.286 (1.30), 7.348 (1.08), 7.364 (1.60), 7.381 (0.74), 7.493 (0.89), 7.509 (1.57), 7.52 8 (0.85 ), 7.547 (0.60), 7.565 (0.90), 7.583 (0.56).

Diastereomer 1: 1.71 g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 - 1.23 (m, 4 H), 1.29 (d, 4 H), 1.36 (s, 8 H), 4.16 (td, 1 H), 4.91 ( br t, 1 H), 5.60 (br d, 1 H), 7.27 (t, 1 H), 7.36 (t, 1 H), 7.48 - 7.61 (m, 2 H).

Diastereomer 2: 1.67 g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (br d, 5 H), 1.29 (d, 4 H), 1.36 (s, 7 H), 2.52 - 2.55 (m, 1 H), 4.10 - 4.21 (m, 1 H), 4.91 (br t, 1 H), 5.56 (d, 1 H), 7.17 - 7.30 (m, 1 H), 7.36 (t, 1 H), 7.48 - 7.59 (m, 2H)

Intermediate 38

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol trifluoroacetic acid (1/1) (diastereomer 1)

Following General Procedure 3: tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]car in DCM (30 ml) Bamate (Intermediate 37, diastereomer 1) (1.70 g, 5.10 mmol) and TFA (5.9 ml, 76 mmol) gave the title compound (2.07 g), which was used without further purification.

LC-MS (Method 2): R _t = 0.83 min; MS (ESIpos): m/z = 234 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.145 (11.32), 1.161 (11.34), 1.223 (2.34), 1.394 (1.43), 1.409 (1.41), 1.501 (16.00), 1.519 (15.96) ), 1.734 (0.86), 2.296 (3.25), 2.518 (3.45), 2.523 (2.51), 4.121 (0.61), 4.139 (0.86), 4.159 (1.08), 4.175 (0.89), 4.196 (0.56), 4.66 9 (1.26 ), 4.684 (1.63), 4.699 (1.26), 7.160 (0.67), 7.164 (0.59), 7.180 (0.86), 7.230 (0.74), 7.248 (0.76), 7.388 (2.16), 7.408 (5.07), 7.42 8 (3.08 ), 7.478 (0.57), 7.522 (1.72), 7.526 (2.00), 7.544 (2.97), 7.559 (1.42), 7.563 (1.33), 7.693 (1.62), 7.710 (2.85), 7.726 (1.45), 8.38 3 (4.21 ).

Intermediate 39

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol trifluoroacetic acid (1/1) (diastereomer 2)

Following General Procedure 3: tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]car in DCM (30 ml) Bamate (Intermediate 37, diastereomer 2) (1.66 g, 4.98 mmol), TFA (5.8 ml) gave the title compound (2.03 g), which was used without further purification.

LC-MS (Method 2): R _t = 0.82 min; MS (ESIpos): m/z = 234 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (11.70), 1.169 (11.66), 1.223 (2.96), 1.406 (1.47), 1.423 (1.47), 1.491 (2.28), 1.503 (16.00) ), 1.520 (15.65), 1.734 (1.13), 2.297 (4.13), 2.336 (0.41), 2.518 (4.38), 2.523 (3.26), 2.678 (0.41), 4.132 (0.63), 4.151 (0.96), 4.1 69 (1.21 ), 4.188 (0.98), 4.207 (0.59), 4.678 (1.30), 4.695 (1.70), 4.708 (1.36), 7.142 (0.42), 7.162 (0.88), 7.164 (0.80), 7.180 (1.03), 7.18 5 (0.62 ), 7.230 (0.91), 7.248 (0.94), 7.391 (2.19), 7.411 (5.20), 7.430 (3.18), 7.484 (0.59), 7.527 (2.00), 7.544 (3.07), 7.560 (1.44), 7.56 4 (1.36 ), 7.699 (1.66), 7.716 (2.97), 7.732 (1.51), 8.360 (4.29).

intermediate 40

(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (diastereomer 1)

According to General Procedure 5: (1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol trifluoride in DCM (25 ml) The title compound (1.17) was obtained from loacetic acid (1/1) (Intermediate 38, 1.57 g, 3.84 mmol), triethylsilyl trifluoromethanesulfonate (4.3 ml, 19 mmol), and 2,6-lutidine (3.1 ml). g, 88% yield) was obtained.

LC-MS (Method 2): R _t = 1.58 min; MS (ESIpos): m/z = 349 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.362 (0.65), 0.379 (0.91), 0.383 (0.83), 0.400 (2.30), 0.407 (0.91), 0.420 (2.51), 0.427 (2.43) ), 0.435 (0.77), 0.440 (1.17), 0.447 (2.63), 0.455 (0.72), 0.466 (1.40), 0.484 (0.72), 0.765 (6.97), 0.772 (0.52), 0.776 (0.71), 0.78 5 (16.00) ), 0.793 (0.72), 0.804 (5.14), 0.873 (0.60), 0.892 (1.24), 0.913 (0.51), 1.189 (2.09), 1.204 (2.12), 1.248 (3.35), 1.265 (3.31), 2.51 8 (0.53 ), 4.241 (0.63), 4.257 (0.62), 7.255 (0.93), 7.274 (0.66), 7.311 (0.43), 7.325 (0.50), 7.329 (0.53), 7.707 (0.51).

Intermediate 41

(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (diastereomer 2)

Following General Procedure 3: trifluoroacetic acid/(1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoropropane- in DCM (25 mL) 2-ol (1/1) (Intermediate 39, 1.53 g, 85% purity, 3.73 mmol), triethylsilyl trifluoromethanesulfonate (4.2 ml, 19 mmol), 2,6-lutidine (3.0 ml) The title compound (1.14 g, 87% yield) was obtained.

LC-MS (Method 2): R _t = 1.58 min; MS (ESIpos): m/z = 349 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.306 (0.93), 0.323 (0.90), 0.326 (1.14), 0.343 (2.11), 0.363 (2.20), 0.383 (1.34), 0.402 (2.03) ), 0.421 (2.25), 0.436 (0.67), 0.440 (1.43), 0.455 (0.72), 0.459 (1.02), 0.478 (0.46), 0.736 (7.05), 0.748 (0.73), 0.756 (16.00), 0.7 65 (0.69 ), 0.776 (5.43), 0.873 (0.54), 0.893 (1.13), 0.913 (0.51), 1.222 (4.18), 1.234 (2.60), 1.238 (3.91), 1.962 (0.54), 2.518 (0.61), 2.52 3 (0.43 ), 4.280 (0.61), 4.296 (0.63), 7.261 (0.91), 7.280 (0.68), 7.327 (0.50), 7.747 (0.50).

Intermediate 42

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2- Methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 1)

Following General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (350 mg, 1.46 mmol), (1R)-1-( 3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (intermediate 40, 608 mg, 1.75 mmol), 2,4, The title compound ( 600 mg, 72% yield) was obtained.

LC-MS (Method 2): R _t = 1.70 min; MS (ESIpos): m/z = 572 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.244 (0.78), 0.261 (0.83), 0.264 (0.99), 0.282 (2.07), 0.302 (2.20), 0.305 (0.85), 0.322 (1.12) ), 0.326 (2.11), 0.345 (2.27), 0.364 (1.37), 0.383 (0.88), 0.402 (0.40), 0.639 (6.53), 0.647 (0.50), 0.650 (0.73), 0.658 (16.00), 0.6 66 (0.70 ), 0.678 (5.04), 1.172 (0.76), 1.189 (0.41), 1.218 (1.90), 1.234 (1.94), 1.589 (2.23), 1.606 (2.23), 1.987 (1.18), 2.411 (7.93), 2.51 8 (0.70 ), 2.523 (0.47), 5.846 (0.52), 7.270 (0.86), 7.289 (0.54), 7.379 (0.49), 7.687 (0.48), 8.658 (1.98), 8.805 (2.35), 8.838 (0.59), 8.85 7 (0.57 ).

Intermediate 43

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2- Methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 2)

Following General Procedure 2: (1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane in DMF (3.7 ml) -1-amine (intermediate 41, 507 mg, 1.46 mmol), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (486 mg, 1.60 mmol), triethylamine (510 μl) ), DMAP (26.7 mg, 219 μmol) was reacted overnight to obtain the title compound (500 mg, 60% yield).

LC-MS (Method 2): R _t = 1.72 min; MS (ESIpos): m/z = 572 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.211 (0.97), 0.228 (0.82), 0.230 (1.11), 0.248 (1.98), 0.268 (1.99), 0.288 (0.80), 0.296 (0.62) ), 0.316 (1.76), 0.336 (1.97), 0.354 (1.32), 0.373 (1.00), 0.392 (0.44), 0.645 (6.51), 0.653 (0.40), 0.656 (0.65), 0.665 (16.00), 0.6 73 (0.67 ), 0.684 (5.07), 1.223 (1.89), 1.239 (1.86), 1.594 (2.22), 1.612 (2.22), 2.371 (7.61), 2.518 (0.43), 5.669 (0.54), 7.244 (0.85), 7.26 3 (0.52 ), 7.371 (0.48), 7.642 (0.47), 8.689 (1.85), 8.797 (2.10), 8.895 (0.54), 8.912 (0.52).

Intermediate 44

(1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl) -1,1-difluoropropan-2-ol (diastereomer 1)

Following General Procedure 3: 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl} in DCM (1.4 ml) From -2-fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 42, 125 mg, 219 μmol) and TFA (250 μl), flash column chromatography The title compound (99.0 mg, 99% yield) was obtained after purification by .

LC-MS (Method 2): R _t = 1.14 min; MS (ESIpos): m/z = 455 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.144 (3.59), 1.154 (1.90), 1.161 (3.59), 1.172 (2.26), 1.190 (1.16), 1.578 (4.44), 1.596 (4.37) ), 1.987 (4.51), 2.399 (16.00), 2.518 (1.66), 2.523 (1.24), 3.320 (0.64), 4.017 (0.96), 4.034 (0.94), 5.563 (2.34), 5.579 (2.28), 5.7 47 (0.68 ), 5.758 (6.34), 5.765 (1.06), 5.782 (0.65), 7.230 (0.72), 7.249 (1.65), 7.269 (0.99), 7.363 (0.54), 7.367 (0.61), 7.384 (0.92), 7.40 0 (0.45 ), 7.404 (0.41), 7.617 (0.52), 7.634 (0.90), 7.651 (0.45), 8.668 (3.75), 8.670 (3.84), 8.807 (4.39), 8.858 (1.09), 8.875 (1.05).

Intermediate 45

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoropropan-2-ol (diastereomer 2)

Following General Procedure 3: 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]propyl} in DCM (5.0 ml) From -2-fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 43, 490 mg, 860 μmol) and TFA (990 μl), flash column chromatography The title compound (351 mg, 90% yield) was obtained after purification by .

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 455 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.131 (3.39), 1.147 (3.45), 1.154 (2.16), 1.171 (3.70), 1.189 (1.77), 1.582 (4.17), 1.600 (4.21) ), 1.986 (5.52), 2.377 (16.00), 2.518 (1.96), 2.523 (1.38), 4.016 (1.11), 4.034 (1.08), 5.578 (2.44), 5.594 (2.37), 5.703 (0.65), 5.7 20 (1.01 ), 5.738 (0.64), 5.756 (2.12), 7.221 (0.70), 7.240 (1.60), 7.259 (0.96), 7.358 (0.51), 7.362 (0.58), 7.380 (0.88), 7.395 (0.44), 7.59 9 (0.49 ), 7.615 (0.86), 7.632 (0.44), 8.666 (3.67), 8.668 (3.68), 8.805 (4.24), 8.875 (1.05), 8.893 (1.00).

Intermediate 46

(1R)-1-{3-[2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoropropyl]-2-fluorophenyl}ethane-1-amine (diastereomer One)

According to General Procedure 5: 1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol trifluoro in DCM (25 ml) Acetic acid (1/1) (Intermediate 38, 1.93 g, 81% purity, 4.47 mmol), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (4.1 ml, 18 mmol) and 2,6-lutidine (3.6 ml), the title compound (1.04 g, 67% yield) was obtained after purification by flash column chromatography.

LC-MS (Method 2): R _t = 1.58 min; MS (ESIpos): m/z = 349 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.225 (4.64), 0.718 (1.04), 0.726 (16.00), 0.733 (1.01), 1.209 (1.33), 1.225 (1.36), 1.260 ( 2.06), 1.276 (2.02), 7.265 (0.56), 7.284 (0.40).

Intermediate 47

6-Bromo-N-[(1R)-1-{3-[2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoropropyl]-2-fluorophenyl}ethyl ]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 1)

Following General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (425 mg, 1.77 mmol) in DMF (5.0 ml), (1R)-1-{ 3-[2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoropropyl]-2-fluorophenyl}ethane-1-amine (Intermediate 46, 738 mg, 2.12 mmol), The title compound (796) was prepared from 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (590 mg, 1.95 mmol), Et ₃ N (620 μl), DMAP (32.4 mg, 266 μmol). mg, 79% yield) was obtained.

LC-MS (Method 2): R _t = 1.73 min; MS (ESIneg): m/z = 567 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.319 (4.72), 0.670 (1.01), 0.678 (16.00), 1.285 (1.28), 1.300 (1.25), 1.643 (1.43), 1.659 ( 1.43), 2.044 (0.75), 2.460 (5.07), 2.575 (0.79), 2.580 (0.56), 7.320 (0.54), 8.714 (1.25), 8.864 (1.44).

Intermediate 48

(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine

According to General Procedure 5: 1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropane-2- in DCM (140 ml) All hydrogen chloride (1/1) [CAS 2569698-46-8] (6.00 g, 21.1 mmol), triethylsilyl trifluoromethanesulfonate (17 ml, 76 mmol), 2,6-lutidine (17 ml) The title compound (7.29 g, 95% yield) was obtained.

LC-MS (Method 2): R _t = 1.66 min; MS (ESIpos): m/z = 363 [M+H] ⁺

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: 0.641 (1.70), 0.662 (6.54), 0.671 (0.47), 0.673 (0.46), 0.682 (7.49), 0.701 (2.64), 0.958 (8.28) ), 0.969 (0.74), 0.978 (16.00), 0.986 (0.76), 0.998 (6.12), 1.544 (4.94), 1.560 (4.89), 1.699 (2.91), 4.560 (1.04), 4.577 (1.02), 7.2 51 (0.47 ), 7.290 (0.64), 7.407 (1.68), 7.438 (0.48), 7.443 (0.52), 7.460 (0.77), 7.475 (0.42), 7.480 (0.41), 7.632 (0.74).

Intermediate 49

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl ]-2-methylpyrido[3,4-d]pyrimidin-4-amine

Following General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (2.50 g, 10.4 mmol) in DMF (25 ml), (1R)-1-( 3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane-1-amine (Intermediate 48, 4.52 g, 12.5 mmol), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (3.47 g, 11.5 mmol), Et ₃ N (5.1 ml, 36 mmol), DMAP (191 mg, 1.56 mmol) Compound (5.30 g, 87% yield) was obtained.

LC-MS (Method 1): R _t = 1.79 min; MS (ESIneg): m/z = 581, 583 [MH] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.87 (d, 1 H), 8.80 (s, 1 H), 8.68 (s, 1 H), 7.62 (t, 1 H), 7.20 - 7.32 ( m, 2 H), 5.73 - 5.80 (m, 1 H), 2.52 - 2.53 (m, 1 H), 2.33 - 2.39 (m, 3 H), 1.58 (d, 3 H), 1.33 (br d, 6) H), 1.23 (br s, 1 H), 0.65 - 0.73 (m, 9 H), 0.38 - 0.48 (m, 6 H).

Intermediate 50

tert-Butyl {(1R)-1-[3-(1,1-difluoro-3,3-dimethyl-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate

tert-Butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl in THF (120 ml) )Ethyl]carbamate (Intermediate 31, 4.34 g, 11.5 mmol) was slowly added to a solution of tert-butyllithium (15 ml, 1.7 M, 25 mmol) at -78°C. The mixture was stirred at -78°C for 1 hour and quenched by addition of saturated aqueous NH ₄ Cl solution at -78°C. The mixture was diluted with water at room temperature, extracted with EtOAc and the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (1.51 g, 35% yield).

LC-MS (Method 2): R _t = 1.51 min; MS (ESIpos): m/z = 374 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.792 (0.90), 1.154 (0.43), 1.172 (0.79), 1.190 (0.44), 1.264 (16.00), 1.279 (3.14), 1.351 (6.23) ), 1.987 (0.76), 2.518 (2.00), 2.523 (1.36), 5.758 (1.57), 7.358 (0.71), 7.377 (0.45), 7.520 (0.55), 7.581 (0.59), 7.600 (0.77).

Intermediate 51

tert-Butyl 4-ethoxy-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate

4-Ethoxy-1,4lambda ⁵ -azaphosphinan-4-one [CAS 1042425-93-3] (20.8 g, 102 mmol) was dissolved in CH ₂ Cl ₂ (300 mL). Triethylamine (43 ml, 310 mmol) was added followed by di-tert-butyl dicarbonate (26 ml, 110 mmol). The mixture was stirred overnight at room temperature. The organic phase was washed with saturated aqueous NaHCO ₃ solution and brine. The organic phase was dried, filtered and the solvent was evaporated to give the title compound (30.7 g, quantitative), which was used in the next step without purification.

LC-MS (Method 2): R _t = 0.86 min; MS (ESIpos): m/z = 264 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.239 (1.89), 1.257 (4.04), 1.275 (1.87), 1.405 (16.00), 3.977 (0.99), 3.994 (1.01), 3.996 (1.06) ), 4.014 (0.90).

Intermediate 52

tert-Butyl 4-oxo-1,4lambda ⁵ -azaphosphinane-1-carboxylate

tert-Butyl 4-ethoxy-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate (Intermediate 51, 26.9 g, 102 mmol) was dissolved in THF (300 mL) and incubated at 0°C. was cooled. Lithium aluminum hydride (82 ml, 1.0 M in THF, 82 mmol) was added dropwise. The mixture was stirred at 0°C for 45 minutes. TLC analysis showed complete consumption of starting material. Half-saturated aqueous Rochelle salt solution was added dropwise. Ethyl acetate was added and the mixture was stirred at room temperature for 1 hour. The suspension was filtered and the organic phase was separated. The aqueous phase was extracted with additional ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The residue was dissolved in CH ₂ Cl ₂ (350 mL) and cooled to 0°C. Hydrogen peroxide (10 ml, 30% purity, 100 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hours. The mixture was cooled to 0° C. and Na ₂ S ₂ O ₃ solution (10 wt%) was added slowly. The mixture was stirred at room temperature for 5 minutes. The organic phase was separated, filtered and the solvent was evaporated. The title compound was purified by flash column chromatography on silica gel using CH ₂ Cl ₂ /EtOH (0% to 10% EtOH). The title compound was obtained as a white solid (21.6 g, 97% yield).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H) 1.63 - 1.88 (m, 2 H) 2.05 - 2.27 (m, 2 H) 3.00 - 3.26 (m, 2 H) 3.78 - 4.09 (m, 2 H) 6.21 - 7.59 (m, 1 H)

Intermediate 53

tert-butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-3,3-dimethylbutyl]-2-fluorophenyl}ethyl]carbamate

tert-Butyl {(1R)-1-[3-(1,1-difluoro-3,3-dimethyl-2-oxobutyl)-2-fluorophenyl]ethyl}carba in EtOH (15 ml) To a solution of mate (Intermediate 50, 1.24 g, 3.32 mmol) was added NaBH ₄ (159 mg, 4.21 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous NH ₄ Cl solution at 0° C., extracted with EtOAc, the organic phase was washed with brine, dried over Na ₂ O ₄ , filtered and concentrated under reduced pressure. Diastereomers were separated by flash column chromatography.

Diastereomer 1: 411 mg (33% yield)

LC-MS (Method 2): R _t = 1.37 min; MS (ESIpos): m/z = 393.6 [M+NH ₄ ⁺ ] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.59 (br d, 1 H), 7.49 (t, 1 H), 7.38 (br t, 1 H), 7.25 (t, 1 H), 5.61 ( d, 1 H), 4.86 - 4.96 (m, 1 H), 3.66 - 3.77 (m, 1 H), 2.52 - 2.54 (m, 1 H), 1.37 (s, 9 H), 1.28 (d, 4 H) ), 0.97 - 1.23 (m, 2 H), 0.94 (s, 9 H), 0.73 - 0.87 (m, 1 H)

Diastereomer 2: 554 mg (44% yield)

LC-MS (Method 2): R _t = 1.36 min; MS (ESIpos): m/z = 393.6 [M+NH ₄ ⁺ ] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.45 - 7.56 (m, 2 H), 7.36 (br t, 1 H), 7.17 - 7.29 (m, 1 H), 5.53 (d, 1 H) , 4.91 (br t, 1 H), 3.66 - 3.77 (m, 1 H), 1.26 - 1.38 (m, 11 H), 1.07 - 1.22 (m, 2 H), 0.96 (s, 9 H)

Intermediate 54

Trifluoroacetic acid/1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (1/1 ) (diastereomer 1)

According to GP 3: tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3,3-dimethylbutyl]-2-fluoro in DCM (7.0 ml) The title compound (626 mg) was obtained from phenyl}ethyl]carbamate (Intermediate 53 (diastereomer 1), 409 mg, 1.09 mmol) and TFA (1.3 ml, 16 mmol), which was used without further purification.

LC-MS (Method 2): R _t = 1.10 min; MS (ESIpos): m/z = 276 [M+H] ⁺

Intermediate 55

Trifluoroacetic acid/1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (1/1 ) (diastereomer 2)

According to General Procedure 3: tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3,3-dimethylbutyl]-2-fluoro in DCM (9.0 ml) Lophenyl}ethyl]carbamate (Intermediate 53 (diastereomer 2), 552 mg, 1.47 mmol) and TFA (1.7 ml, 22 mmol) gave the title compound (787 mg), which was used without further purification. .

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 276 [M+H] ⁺

Intermediate 56

(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethan-1-amine (partial Stereoisomer 1)

According to GP 6: 1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutane-2 in DCM (7.0 ml) -ol trifluoroacetic acid (1/1) (intermediate 54, 626 mg, 1.09 mmol), triethylsilyl trifluoromethanesulfonate (1.2 ml, 5.4 mmol) and 2,6-lutidine (880 μl) The title compound (702 mg) was obtained and used without further purification.

LC-MS (Method 2): R _t = 1.78 min; MS (ESIpos): m/z = 390 [M+H] ⁺

Intermediate 57

(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethan-1-amine (partial Stereoisomer 2)

According to General Procedure 5: 1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutane- in DCM (10 ml) 2-ol trifluoroacetic acid (1/1) (intermediate 55, 787 mg, 1.47 mmol), triethylsilyl trifluoromethanesulfonate (1.7 ml, 7.3 mmol), 2,6-lutidine (1.2 ml) The title compound (786 mg) was obtained, which was used without further purification.

LC-MS (Method 2): R _t = 1.78 min; MS (ESIpos): m/z = 390 [M+H] ⁺

Intermediate 58

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl )Ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 1)

Following General Procedure 2: (1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2 in DMF (3.5 ml) -Fluorophenyl)ethan-1-amine (intermediate 56, 702 mg, 1.08 mmol), 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (286 mg, 1.19 mmol) ), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (394 mg, 1.30 mmol), Et ₃ N (380 μl), DMAP (19.9 mg, 163 μmol). (399 mg, 60% yield) was obtained.

LC-MS (Method 2): R _t = 1.89 min; MS (ESIpos): m/z = 611 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.382 (0.45), 0.399 (0.83), 0.419 (2.32), 0.434 (2.46), 0.440 (2.56), 0.453 (2.53), 0.459 (1.07) ), 0.473 (1.14), 0.491 (0.45), 0.814 (11.81), 0.820 (10.17), 0.831 (1.20), 0.839 (16.00), 0.847 (1.16), 0.859 (5.87), 1.154 (0.64), 1 .172 (1.37 ), 1.190 (0.71), 1.583 (2.69), 1.600 (2.66), 1.987 (2.29), 2.331 (0.66), 2.388 (9.60), 2.518 (2.97), 2.523 (2.15), 2.673 (0.65), 4.01 7 (0.69 ), 4.035 (0.62), 4.047 (0.55), 5.746 (0.42), 5.763 (0.64), 5.782 (0.40), 7.261 (0.52), 7.280 (1.12), 7.299 (0.66), 7.446 (0.58), 7.67 6 (0.58 ), 8.670 (2.35), 8.809 (2.60), 8.847 (0.71), 8.865 (0.69).

Intermediate 59

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl )Ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 2)

Following General Procedure 2: (1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethylsilyl)oxy]butyl}-2 in DMF (5.0 ml) -Fluorophenyl)ethan-1-amine (intermediate 57, 786 mg, 1.47 mmol), 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (388 mg, 1.62 mmol) ), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (534 mg, 1.76 mmol), Et ₃ N (510 μl), DMAP (26.9 mg, 220 μmol). (683 mg, 76% yield) was obtained.

LC-MS (Method 2): R _t = 1.89 min; MS (ESIpos): m/z = 611 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.323 (0.62), 0.342 (0.86), 0.360 (2.06), 0.369 (0.83), 0.380 (2.24), 0.389 (2.16), 0.400 (1.00) ), 0.409 (2.27), 0.428 (1.19), 0.447 (0.71), 0.795 (7.39), 0.807 (1.10), 0.815 (16.00), 0.824 (1.10), 0.835 (6.59), 0.850 (11.81), 1. 154 (0.73 ), 1.172 (1.60), 1.190 (0.83), 1.591 (2.84), 1.609 (2.81), 1.987 (2.97), 2.361 (9.68), 2.518 (2.34), 2.523 (1.67), 4.017 (0.68), 4.03 5 (0.96 ), 4.072 (0.56), 5.630 (0.45), 5.648 (0.69), 5.666 (0.44), 7.237 (0.56), 7.256 (1.21), 7.275 (0.71), 7.432 (0.62), 7.641 (0.61), 8.69 9 (2.47 ), 8.802 (2.82), 8.915 (0.73), 8.933 (0.71).

intermediate 60

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 1)

Following General Procedure 3: 6-bromo-N-[(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethyl) in DCM (3.0 ml) Silyl)oxy]butyl}-2-fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 58, 197 mg, 322 μmol) and TFA (500 μl) The title compound (162 mg, quantitative) was obtained.

LC-MS (Method 2): R _t = 1.35 min; MS (ESIpos): m/z = 497 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (16.00), 1.154 (1.39), 1.172 (3.14), 1.190 (1.63), 1.572 (3.80), 1.590 (3.78), 1.987 (5.39) ), 2.382 (0.46), 2.411 (13.54), 2.518 (2.04), 2.523 (1.45), 4.017 (1.23), 4.035 (1.23), 4.053 (0.40), 5.537 (1.83), 5.556 (1.82), 5.7 49 (0.61 ), 5.759 (6.90), 5.767 (0.94), 5.784 (0.58), 7.219 (0.68), 7.238 (1.51), 7.258 (0.88), 7.383 (0.52), 7.400 (0.83), 7.416 (0.40), 7.60 5 (0.45 ), 7.621 (0.80), 7.638 (0.41), 8.681 (3.21), 8.683 (3.31), 8.811 (3.75), 8.850 (0.98), 8.869 (0.96).

Intermediate 61

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 2)

Following General Procedure 3: 6-bromo-N-[(1R)-1-(3-{1,1-difluoro-3,3-dimethyl-2-[(triethyl) in DCM (5.0 ml) Silyl)oxy]butyl}-2-fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 59, 340 mg, 556 μmol) and TFA (860 μl) The title compound (285 mg, quantitative) was obtained.

LC-MS (Method 2): R _t = 1.34 min; MS (ESIpos): m/z = 497 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (10.60), 1.154 (1.12), 1.172 (2.25), 1.189 (1.06), 1.583 (2.52), 1.600 (2.50), 1.987 (3.85) ), 2.084 (16.00), 2.382 (8.95), 2.518 (0.89), 2.523 (0.62), 4.016 (0.79), 4.034 (0.76), 5.570 (1.00), 5.589 (0.99), 5.737 (0.56), 5.7 59 (1.82 ), 7.203 (0.46), 7.222 (1.01), 7.241 (0.60), 7.398 (0.55), 7.591 (0.53), 8.672 (2.13), 8.805 (2.45), 8.860 (0.61), 8.878 (0.59).

Intermediate 62

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-one trifluoroacetic acid (1/1)

Following General Procedure 3: tert-butyl {(1R)-1-[3-(1,1-difluoro-3,3-dimethyl-2-oxobutyl)-2-fluoro in DCM (4 ml) The title compound (284 mg) was obtained from phenyl]ethyl}carbamate (intermediate 50, 200 mg, 536 μmol) and TFA (410 μl, 5.4 mmol).

LC-MS (Method 2): R _t = 1.20 min; MS (ESIpos): m/z = 274 [M+H] ⁺

Intermediate 63

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-3,3-dimethylbutan-2-one

Following General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 141 mg, 589 μmol), 1-{3) in DMF (3 ml) -[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-one trifluoroacetic acid (1/1) (Intermediate 62, 284 mg, 535 μmol), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (195 mg, 642 μmol), Et ₃ N (220 μl, 1.6 mmol), DMAP (13.1 mg, 107 μmol) and additional DIPEA (370 μl, 2.1 mmol) to give the title compound (217 mg, 74% yield).

LC-MS (Method 2): R _t = 144.00 min; MS (ESIpos): m/z = 495 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.90 (d, 1 H), 8.81 (s, 1 H), 8.66 (d, 1 H), 7.70 (t, 1 H), 7.54 (t, 1 H), 7.30 - 7.38 (m, 1 H), 5.60 - 5.72 (m, 1 H), 2.52 - 2.54 (m, 2 H), 2.33 - 2.39 (m, 3 H), 1.58 (d, 3 H) ), 1.15 - 1.28 (m, 9 H), 0.73 (s, 1 H)

Intermediate 64

2-{(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}-1H-isoindole-1,3( 2H)-Dion

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol hydrogen chloride (1/1) in THF (50 ml) ) (500 mg, 1.76 mmol), Et ₃ N (980 μl, 7.0 mmol) and DMAP (10.8 mg, 0.088 mmol) were added to 2-benzofuran-1,3-dione (313 mg, 2.11 mmol). did. The mixture was stirred at room temperature overnight and then heated to 70°C overnight. Ac ₂ O (170 μl, 1.8 mmol) was then added at room temperature and the mixture was heated to 70° C. for 3 days. The mixture was washed with saturated aqueous NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (584 mg, 88% yield).

LC-MS (Method 2): R _t = 1.21 min; MS (ESIpos): m/z = 378 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.101 (7.88), 1.151 (7.99), 1.172 (2.27), 1.190 (1.14), 1.786 (6.84), 1.804 (6.76), 1.987 (3.89) ), 2.518 (2.26), 2.523 (1.58), 4.017 (0.90), 4.035 (0.89), 5.311 (9.06), 5.658 (0.42), 5.677 (1.47), 5.694 (1.44), 5.713 (0.41), 5.75 9 (1.22 ), 7.280 (0.84), 7.299 (2.09), 7.319 (1.40), 7.365 (0.86), 7.369 (0.98), 7.386 (1.33), 7.402 (0.61), 7.406 (0.57), 7.742 (0.72), 7.75 9 (1.30 ), 7.775 (0.66), 7.839 (1.58), 7.848 (16.00), 7.851 (8.12), 7.856 (1.47).

intermediate 65

2-{(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}-1H-isoindole-1,3( 2H)-Dion

2-{(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]-ethyl}-1H- in DMF (10 ml) To a solution of isoindole-1,3(2H)-dione (intermediate 64, 580 mg, 1.54 mmol) was added NaH (61.5 mg, 60% purity, 1.54 mmol) and the mixture was stirred at room temperature for 30 minutes. Iodomethane (190 μl, 3.1 mmol) was added and the reaction was stirred for 1 hour. Additional iodomethane (190 μl, 3.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (443 mg, 74% yield).

LC-MS (Method 2): R _t = 1.39 min; MS (ESIpos): m/z = 392 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (7.38), 1.177 (7.28), 1.190 (0.91), 1.784 (6.43), 1.802 (6.39), 1.987 (1.73), 2.074 (1.51) ), 2.518 (5.25), 2.523 (3.51), 2.678 (0.40), 3.078 (16.00), 4.017 (0.41), 5.673 (1.28), 5.691 (1.25), 5.759 (2.25), 7.283 (0.72), 7.3 03 (1.86 ), 7.322 (1.29), 7.357 (0.80), 7.362 (0.95), 7.379 (1.20), 7.395 (0.55), 7.399 (0.50), 7.747 (0.61), 7.764 (1.13), 7.780 (0.58), 7.83 8 (1.39 ), 7.847 (13.01), 7.849 (12.83), 7.851 (7.10), 7.857 (1.46).

Intermediate 66

(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethane-1-amine

2-{(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl] in EtOH (5.5 ml) and THF (5.5 ml) To a solution of ethyl}-1H-isoindole-1,3(2H)-dione (Intermediate 65, 440 mg, 1.12 mmol) was added hydrazine hydrate (550 μl, 11 mmol) and the mixture was stirred at room temperature overnight. The resulting suspension was filtered and the residue was washed with EtOH/DCM. The residue was dissolved in DCM/H ₂ O and the organic phase was washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and combined with the concentrated filtrate. Purification by flash column chromatography gave the title compound (270 mg, 92% yield).

LC-MS (Method 2): R _t = 1.10 min; MS (ESIpos): m/z = 262 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (15.13), 1.240 (15.59), 2.332 (0.42), 2.518 (1.96), 2.523 (1.37), 2.673 (0.41), 3.185 (16.00) ), 4.242 (0.44), 4.258 (1.39), 4.275 (1.37), 4.291 (0.43), 7.214 (0.53), 7.233 (1.74), 7.251 (2.39), 7.255 (2.00), 7.265 (1.15), 7.27 0 (1.36 ), 7.285 (0.55), 7.290 (0.42), 7.688 (0.53), 7.694 (0.62), 7.705 (1.02), 7.711 (1.05), 7.723 (0.56), 7.728 (0.56).

Intermediate 67

6-Bromo-N-{(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}-2-methylpyri nor[3,4-d]pyrimidin-4-amine

According to General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 205 mg, 854 μmol), (1R)- in DMF (3.0 ml) 1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethane-1-amine (Intermediate 66, 268 mg, 1.02 mmol), 2,4 The title compound (285) was prepared from 6-tri(propan-2-yl)benzene-1-sulfonyl chloride (284 mg, 939 μmol), Et ₃ N (360 μl, 2.6 mmol), DMAP (20.9 mg, 171 μmol) mg, 69% yield) was obtained.

LC-MS (Method 2): R _t = 1.39 min; MS (ESIpos): m/z = 483 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.71), 1.247 (5.99), 1.255 (6.17), 1.572 (4.29), 1.589 (4.32), 1.987 (0.99), 2.332 (0.46) ), 2.370 (16.00), 2.518 (2.44), 2.523 (1.71), 2.673 (0.47), 3.174 (12.80), 3.349 (0.96), 5.704 (0.65), 5.722 (1.03), 5.740 (0.65), 7. 202 (0.60 ), 7.221 (1.45), 7.240 (0.97), 7.291 (0.58), 7.295 (0.68), 7.312 (0.91), 7.328 (0.44), 7.590 (0.50), 7.606 (0.87), 7.622 (0.45), 8.67 8 (3.74 ), 8.805 (4.39), 8.877 (1.04), 8.895 (1.00).

Intermediate 68

(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoro-2-methylpropyl)-2-fluorophenyl]-ethane-1- amine

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol hydrogen chloride (1/1) (2.00 g, 7.05 mmol) was dissolved in CH2Cl2 (40 mL) and cooled to 0° C. under argon atmosphere. Lutidine (5.7 ml) was added and the resulting mixture was stirred for 5 minutes. tert-Butyl(dimethyl)silyl trifluoromethanesulfonate (6.5 ml, 28 mmol) was added dropwise and the mixture was allowed to slowly warm to room temperature overnight. Saturated aqueous NaHCO3 solution was added and the mixture was stirred for 10 minutes. The organic phase was separated and dried. The solvent was evaporated at elevated temperature. Toluene was added and the solvent was evaporated again. The title compound was purified by flash column chromatography on silica gel to give the title compound (2.07 g, 81% yield).

LC-MS (Method 2): R _t = 1.65 min; MS (ESIpos): m/z = 363 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.013 (0.48), 0.766 (1.23), 0.773 (16.00), 0.780 (0.95), 0.839 (1.21), 1.222 (2.07), 1.238 ( 2.05), 1.316 (3.78), 2.518 (0.79), 2.523 (0.53), 7.229 (0.50), 7.248 (0.42).

Intermediate 69

6-Bromo-N-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoro-2-methylpropyl)-2-fluoro lophenyl]ethyl}-2-methylpyrido[3,4-d]pyrimidin-4-amine

6-Bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 200 mg, 833 μmol) and (1R)-1-[3-(2-{[tert- Butyl(dimethyl)silyl]oxy}-1,1-difluoro-2-methylpropyl)-2-fluorophenyl]-ethane-1-amine (Intermediate 68, 452 mg, 1.25 mmol) was dissolved in DMF (6.4 mL) ) was dissolved in PyBop (564 mg, 1.08 mmol) was added followed by DBU (500 μl, 3.3 mmol) and the resulting mixture was stirred at room temperature for 1 night. Ethyl acetate was added. The organic phase was washed with water (twice) and brine and dried. The solvent was evaporated. The title compound was purified by flash column chromatography on silica gel to give the title compound (330 mg, 68% yield).

LC-MS (Method 2): R _t = 1.79 min; MS (ESIpos): m/z = 586 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.804 (1.02), 0.811 (16.00), 0.819 (0.90), 1.249 (0.87), 1.267 (1.83), 1.285 (0.89), 1.434 (2.40) ), 1.668 (1.48), 1.685 (1.48), 2.083 (3.06), 2.455 (5.25), 2.614 (0.63), 2.618 (0.44), 4.112 (0.67), 4.130 (0.65), 7.310 (0.51), 8.77 1 (1.25 ), 8.773 (1.27), 8.897 (1.48).

intermediate 70

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-2-methylpropan-2-ol

6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)- Ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (Intermediate 69, 400 mg, 685 μmol) was dissolved in CH2Cl2 (6 mL) at room temperature. Triethyl silane (11 μl, 69 μmol) was added followed by trifluoroacetic acid (790 μl, 10 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 night. Toluene was added and the solvent was evaporated. The title compound was purified by flash column chromatography on silica gel to give the title compound (340 mg, 106% yield).

LC-MS (Method 2): R _t = 1.21 min; MS (ESIpos): m/z = 471 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.201 (9.34), 1.221 (9.52), 1.599 (6.66), 1.616 (6.61), 2.442 (16.00), 2.518 (6.01), 2.523 (3.93) ), 3.165 (6.91), 4.016 (0.42), 4.035 (0.41), 5.759 (8.13), 5.770 (1.06), 5.788 (1.58), 5.806 (1.01), 7.228 (1.02), 7.247 (2.42), 7.26 6 (1.56 ), 7.331 (1.09), 7.348 (1.57), 7.363 (0.73), 7.614 (0.88), 7.631 (1.55), 7.646 (0.78), 8.744 (4.93), 8.845 (6.52).

Intermediate 71

6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-ol

6-Chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 5.00 g, 25.6 mmol) and tetrakis (4.68 g, 5.11 mmol) in acetonitrile (130 mL) dissolved. Triethyl amine (12 ml, 89 mmol) was added followed by dimethyl-lambda ⁵ -phosphanone (2.00 g, 25.6 mmol). The mixture was heated to 90° C. for 48 hours. The solid formed was collected by filtration and washed with MTBE to give the title compound as a light gray solid (6.68 g, 82% purity, 90% yield).

LC-MS (Method 1): R _t = 0.50 min; MS (ESIpos): m/z = 238 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (3.14), 1.675 (15.74), 1.708 (16.00), 2.075 (0.76), 2.426 (14.14), 2.518 (2.02), 2.523 (1.48) ), 3.073 (1.07), 8.385 (1.83), 8.388 (1.88), 8.400 (1.88), 8.402 (1.79), 9.108 (3.17).

Intermediate 72

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate

tert-Butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl)ethyl]carbamate (Intermediate 31, 501 mg, 1.33 mmol) was dissolved in THF (15 mL) at room temperature under nitrogen atmosphere. Ethyl magnesium bromide solution (1.2 ml, 3.2 M, 4.0 mmol) was added slowly and the mixture was stirred at room temperature for 3 hours. Saturated aqueous NH ₄ Cl solution was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried and the solvent was evaporated to give the title compound as a yellow oil (440 mg, 96% yield).

LC-MS (Method 2): R _t = 1.34 min; MS (ESIpos): m/z = 363 [M+NH ₄ ] ⁺

Intermediate 74

tert-butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxybutyl]-2-fluorophenyl}ethyl]carbamate (mixture of diastereomers )

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate (2.76 g, 7.99 mmol) was dissolved in ethanol (31 mL). The atmosphere was changed to argon and the mixture was cooled to 0°C. Sodium borohydride (453 mg, 12.0 mmol) was added little by little. The mixture was allowed to warm to room temperature. The mixture was added to half-saturated aqueous NH4Cl solution. Stirred at RT for 1 hour. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine. The organic phase was separated, dried and the solvent was evaporated to give a colorless oil. The title compound was purified by HPLC separation to give a colorless oil (1.09 g, 39% yield).

LC-MS (Method 2): R _t = 1.24 min; MS (ESIpos): m/z = 365 [M+NH ₄ ] ⁺

The two diastereomers of intermediate 72 were separated by chiral HPLC.

Analysis method:

Instrument: Agilent: 1260, Aurora SFC-module; Column: Chiralpak IG 3 μ 100x4.6mm; Eluent A: CO2; Eluent B: methanol + 0.2 vol % aqueous ammonia (32%); Isocratic: 7%B; Gradient: None; Flow rate: 4 ml/min; Temperature: 37.5℃; BPR: 100bar; UV: 262 nm

For purification - method: SFC

Instrument: Sepiatec: SFC100 for purification; Column: Chiralpak IG 5 μ 250x30mm; Eluent A: CO2; Eluent B: methanol; Isocratic: 7%B; Gradient: None; Flow rate: 100 ml/min; Temperature: 40℃; BPR: 150bar; UV: 262nm

Intermediate 73

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxybutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 1)

Diastereomer 1 of Intermediate 72:

Rt (method) = 0.80 minutes

Intermediate 75

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxybutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 2)

Diastereomer 2 of Intermediate 72:

Rt (method) = 1.17 minutes

Intermediate 76

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol trifluoroacetic acid (1/1) (diastereomer 1)

tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxybutyl]-2-fluorophenyl}ethyl]carbamate (Intermediate 74, 549 mg, 1.58 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) at room temperature. Trifluoroacetic acid (2.0 ml, 26 mmol) was added and the mixture was stirred at room temperature for 3 hours. Toluene was added and the solvent was evaporated to give a colorless oil (615 mg), which was used without further purification.

LC-MS (Method 2): R _t = 0.90 min; MS (ESIpos): m/z = 248 [M+H] ⁺

Intermediate 77

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol trifluoroacetic acid (1/1) (diastereomer 2)

tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxybutyl]-2-fluorophenyl}ethyl]carbamate (Intermediate 75, 692 mg, 1.99 mmol) was dissolved in CH ₂ Cl ₂ (5 mL). Trifluoroacetic acid (2.0 ml, 26 mmol) was added and the mixture was stirred at room temperature for 3 hours. Toluene was added to the mixture and the solvent was evaporated to give the title compound as a colorless oil (859 mg), which was used without further purification.

LC-MS (Method 2): R _t = 0.88 min; MS (ESIpos): m/z = 248 [M+H] ⁺

Intermediate 78

(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethane-1-amine (diastereomer 1)

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol trifluoroacetic acid (1/1) (Intermediate 76, 615 mg , 1.70 mmol) was dissolved in CH ₂ Cl ₂ (7.6 mL) and 2,6-lutidine (1.4 mL) was added. The mixture was stirred at room temperature for 10 minutes. Triethylsilyl trifluoromethanesulfonate (2.25 g, 8.51 mmol) was added dropwise, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. Saturated aqueous NaHCO ₃ was added. The phases were separated, the organic phase was dried and the solvent was evaporated. Toluene was added and the solvent was evaporated again. This step was repeated. The title compound was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9/1 to 0/10) as eluent. The title compound was obtained as a light yellow oil (387 mg, 63% yield).

LC-MS (Method 2): R _t = 1.66 min; MS (ESIpos): m/z = 362.5 [M+H] ⁺

Intermediate 79

(1R)-1-(3-{1,1-difluoro-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethane-1-amine (diastereomer 2)

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol trifluoroacetic acid (1/1) (Intermediate 77, 859 mg , 2.38 mmol) was dissolved in CH ₂ Cl ₂ (11 mL). 2,6-lutidine (1.9 mL) was added. Triethylsilyl trifluoromethanesulfonate (3.14 g, 11.9 mmol) was added dropwise, and the mixture was stirred at room temperature under nitrogen atmosphere for 6 hours. Saturated aqueous NaHCO ₃ solution was added and the mixture was stirred for 10 minutes. The organic phase was separated and dried. The solvent was evaporated. Toluene was added and the solvent was evaporated. The steps were repeated again. The title compound was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9/1 to 0/10) as eluent. The title compound was obtained as a light yellow oil (466 mg, 54% yield).

LC-MS (Method 2): R _t = 1.63 min; MS (ESIpos): m/z = 362.9 [M+H] ⁺

intermediate 80

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxohexyl)-2-fluorophenyl]ethyl}carbamate

n-Butyllithium (1.6 ml, 2.5 M, 4.0 mmol) was diluted in THF (4 mL) under argon, cooled to -78°C and stirred for 15 min. tert-Butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl)ethyl]carbamate (Intermediate 31, 500 mg, 1.33 mmol) was dissolved in THF (4 mL) and added to this solution. The mixture was stirred at -78°C for 1 hour and then allowed to slowly warm to room temperature overnight. Saturated aqueous NH4Cl solution was added dropwise. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried and the solvent was evaporated. The title compound was purified by flash column chromatography on silica gel. The title compound was obtained (300 mg, 60% yield).

LC-MS (Method 2): R _t = 1.72 min; MS (ESIpos): m/z = 490 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.818 (5.29), 0.836 (13.01), 0.854 (6.33), 1.154 (0.98), 1.212 (0.67), 1.230 (1.83), 1.248 (2.89) ), 1.253 (1.78), 1.265 (8.18), 1.282 (7.11), 1.305 (0.92), 1.349 (16.00), 1.488 (0.69), 1.505 (1.88), 1.525 (2.29), 1.543 (1.66), 1.5 60 (0.50 ), 2.073 (0.65), 2.327 (0.63), 2.331 (0.45), 2.518 (2.99), 2.523 (1.95), 2.669 (0.63), 2.673 (0.45), 2.784 (1.93), 2.801 (3.60), 2.81 9 (1.77 ), 4.841 (0.51), 4.859 (0.69), 4.876 (0.47), 7.355 (0.79), 7.374 (1.80), 7.394 (1.12), 7.534 (0.96), 7.551 (1.56), 7.571 (1.07), 7.57 8 (0.95 ), 7.595 (1.42), 7.610 (1.61), 7.628 (0.74).

Intermediate 81

tert-Butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-2-methylhexyl]-2-fluorophenyl}ethyl]carbamate (partial mixture of stereoisomers)

tert-butyl {(1R)-1-[3-(1,1-difluoro-2-oxohexyl)-2-fluorophenyl]ethyl}carbamate (Intermediate 80, 297 mg, 795 μmol) Dissolve in THF (12 mL) under argon atmosphere and cool to 0°C. Methyl magnesium bromide solution (700 μl, 3.4 M, 2.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes and then allowed to slowly warm to room temperature overnight. The mixture was cooled to 0° C. and saturated aqueous NH ₄ Cl solution was added slowly. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried and the solvent was evaporated. The title compound was purified by flash column chromatography on silica gel. The title compound was obtained (278 mg, 90% yield).

LC-MS (Method 2): R _t = 1.40 min; MS (ESIpos): m/z = 407 [M+H]+NH3 ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.834 (1.53), 0.841 (1.59), 0.852 (4.39), 0.859 (2.93), 0.869 (2.28), 0.876 (1.42), 1.116 (3.42) ), 1.132 (3.59), 1.154 (0.68), 1.172 (1.35), 1.190 (1.01), 1.232 (1.31), 1.250 (1.90), 1.267 (5.23), 1.284 (4.60), 1.359 (16.00), 1.4 21 (0.51 ), 1.461 (0.92), 1.482 (0.74), 1.987 (1.03), 2.518 (2.06), 2.523 (1.39), 4.879 (0.48), 4.897 (0.65), 4.915 (0.44), 5.176 (3.63), 5.18 5 (2.26 ), 5.758 (5.62), 7.220 (0.60), 7.239 (1.59), 7.258 (1.29), 7.284 (0.93), 7.299 (1.19), 7.316 (0.51), 7.465 (0.69), 7.480 (1.21), 7.49 7 (0.65 ), 7.528 (0.50), 7.538 (0.62), 7.547 (0.60), 7.558 (0.52).

intermediate 82

Trifluoroacetic acid/(2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol (1 /1) (mixture of diastereomers)

tert-butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-2-methylhexyl]-2-fluorophenyl}ethyl]carbamate (50.0 mg, 128 μmol) was dissolved in CH ₂ Cl ₂ (1 mL) at room temperature under argon atmosphere. Trifluoroacetic acid (99 μl, 1.3 mmol) was added and the mixture was stirred at room temperature overnight. Toluene was added and the solvent was evaporated. Toluene was added again and the solvent was evaporated to give the title compound (64.0 mg), which was used without further purification.

LC-MS (Method 2): R _t = 1.14 min; MS (ESIpos): m/z = 290 [M+H] ⁺

Intermediate 83

tert-Butyl {(1R)-1-[3-(1,1-difluoro-3-methyl-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate

According to General Procedure 4: tert-butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl )Ethyl]carbamate (Intermediate 31, 2.76 g, 7.34 mmol) and chlorido(propan-2-yl)magnesium (11 ml, 2.0 M, 22 mmol) were reacted for 5 hours to obtain the title compound (773 mg, 29 % yield) was obtained as an oil.

LC-MS (Method 2): R _t = 1.38 min; MS (ESIneg): m/z = 358.5 (MH) ^- .

¹ H NMR (400 MHz, chloroform-d) δ ppm 1.14 - 1.63 (m, 22 H), 3.20 - 3.38 (m, 1 H), 4.81 - 5.07 (m, 2 H), 7.18 - 7.25 (m, 1) H), 7.39 - 7.47 (m, 1 H), 7.48 - 7.57 (m, 1 H).

Intermediate 84

Trifluoroacetic acid/1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-one (1/1)

Following general procedure 3: tert-butyl {(1R)-1-[3-(1,1-difluoro-3-methyl-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate ( Intermediate 83, 288 mg, 801 μmol) and TFA (620 μl, 8.0 mmol) gave the title compound as an oil (312 mg, quantitative), which was used without further purification.

LC-MS (Method 2): R _t = 1.17 min; MS (ESIpos): m/z = 260.4 [M+H] ⁺ .

intermediate 85

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 1,1-difluoro-3-methylbutan-2-one

According to General Procedure 2: 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (204 mg, 852 μmol) in DMF (3.0 ml), trifluoroacetic acid/1- {3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-one (1/1) (289 mg, 774 μmol), From 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (281 mg, 929 μmol), DMAP (18.9 mg, 155 μmol) and additional DIPEA (540 μl, 3.1 mmol), The title compound (259.0 mg, 63%) was obtained as a white solid after purification by flash column chromatography (hexane/EtOAc).

LC-MS (Method 2): R _t = 1.38 min; MS (ESIpos): m/z = 481.5, 483.4 [M+H] ⁺

intermediate 86

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 1)

tert-butyl {(1R)-1-[3-(1,1-difluoro-3-methyl-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate (Intermediate 85, 5.96 g, 16.6 mmol) was dissolved in ethanol (65 mL). The atmosphere was changed to argon and the mixture was cooled to 0°C. NaBH ₄ (942 mg, 24.9 mmol) was added in portions. The mixture was allowed to warm to room temperature. The mixture was added to half-saturated aqueous NH ₄ Cl solution and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine. The organic phase was separated, dried and the solvent was evaporated to give a colorless oil. The title compound was purified by HPLC separation to give a colorless oil (3.37 g, 56% yield).

The two diastereomers were separated by chiral HPLC. Diastereomer 1 was obtained as the first eluting isomer.

LC-MS (Method 2): R _t = 1.28 min; MS (ESIpos): m/z = 379.6 [M+NH ₄ ] ⁺

Intermediate 87

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 2)

After separation of the two diastereomers of intermediate 86, diastereomer 2 was obtained as the second eluting isomer.

LC-MS (Method 2): R _t = 1.26 min; MS (ESIpos): m/z = 379.6 [M+NH ₄ ] ⁺

intermediate 88

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol trifluoroacetic acid (1/1) (partial Stereoisomer 1)

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3-methylbutyl]-2-fluorophenyl}ethyl]-carbamate (Intermediate 86, 286 mg, 791 μmol) was dissolved in CH ₂ Cl ₂ (5 mL) at room temperature. Trifluoroacetic acid (2.0 ml, 26 mmol) was added and the mixture was stirred at room temperature for 3 hours. Toluene was added and the solvent was evaporated to give the title compound as a colorless oil (295 mg, 99% yield).

LC-MS (Method 2): R _t = 1.01 min; MS (ESIpos): m/z = 262.6 [M+H] ⁺

Intermediate 89

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol trifluoroacetic acid (1/1) (partial Stereoisomer 2)

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy-3-methylbutyl]-2-fluorophenyl}ethyl]-carbamate (Intermediate 87, 297 mg, 822 μmol) was dissolved in CH ₂ Cl ₂ (5 mL) at room temperature. Trifluoroacetic acid (2.0 ml, 26 mmol) was added and the mixture was stirred for 3 hours. Toluene was added and the solvent was evaporated to give a colorless oil (339 mg), which was used without further purification.

LC-MS (Method 2): R _t = 0.99 min; MS (ESIpos): m/z = 262.6 [M+H] ⁺

intermediate 90

(1R)-1-(3-{1,1-difluoro-3-methyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethane-1-amine (diastereomer One)

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol trifluoroacetic acid (1/1) (Intermediate 88, 295 mg, 786 μmol) was dissolved in CH ₂ Cl ₂ (3.5 mL) and 2,6-lutidine (0.64 mL) was added. The mixture was stirred at room temperature for 10 minutes. Triethylsilyl trifluoromethanesulfonate (1.04 g, 3.93 mmol) was added dropwise, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. Saturated aqueous NaHCO ₃ was added. The phases were separated, the organic phase was dried and the solvent was evaporated. Toluene was added and the solvent was evaporated again. This step was repeated. The title compound was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9/1 to 0/10) as eluent. The title compound was obtained as a light yellow oil (197 mg, 67% yield).

LC-MS (Method 2): R _t = 1.73 min; MS (ESIpos): m/z = 376.9 [M+H] ⁺

intermediate 91

(1R)-1-(3-{1,1-difluoro-3-methyl-2-[(triethylsilyl)oxy]butyl}-2-fluorophenyl)ethane-1-amine (diastereomer 2)

1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol trifluoroacetic acid (1/1) (Intermediate 89, 339 mg, 903 μmol) was dissolved in CH2Cl2 (4 mL) and rutidine (0.74 mL) was added. The mixture was stirred at room temperature for 10 minutes. Triethylsilyl trifluoromethanesulfonate (1.19 g, 4.52 mmol) was added dropwise, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. Saturated aqueous NaHCO ₃ was added. The phases were separated, the organic phase was dried and the solvent was evaporated. Toluene was added and the solvent was evaporated again. This step was repeated. The title compound was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9/1 to 0/10) as eluent. The title compound was obtained as a light yellow oil (201 mg, 59% yield).

LC-MS (Method 2): R _t = 1.72 min; MS (ESIpos): m/z = 376.8 [M+H] ⁺

intermediate 92

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxohexyl)-2-fluorophenyl]ethyl}carbamate

tert-Butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2-fluorophenyl in THF (8.0 ml) ) Butyllithium (1.6 ml, 2.5 M, 4.0 mmol) was added dropwise to a solution of ethyl] carbamate (500 mg, 1.33 mmol) at -78°C. The reaction was stirred at -78°C for 1 hour and allowed to warm to room temperature overnight. The reaction was quenched by addition of aqueous ammonium chloride solution. The mixture was extracted twice with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (300 mg, 95% purity, 60% yield).

LC-MS (Method 2): R _t = 1.72 min; MS (ESIpos): m/z = 490 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.818 (5.29), 0.836 (13.01), 0.854 (6.33), 1.154 (0.98), 1.212 (0.67), 1.230 (1.83), 1.248 (2.89) ), 1.253 (1.78), 1.265 (8.18), 1.282 (7.11), 1.305 (0.92), 1.349 (16.00), 1.488 (0.69), 1.505 (1.88), 1.525 (2.29), 1.543 (1.66), 1.5 60 (0.50 ), 2.073 (0.65), 2.327 (0.63), 2.331 (0.45), 2.518 (2.99), 2.523 (1.95), 2.669 (0.63), 2.673 (0.45), 2.784 (1.93), 2.801 (3.60), 2.81 9 (1.77 ), 4.841 (0.51), 4.859 (0.69), 4.876 (0.47), 7.355 (0.79), 7.374 (1.80), 7.394 (1.12), 7.534 (0.96), 7.551 (1.56), 7.571 (1.07), 7.57 8 (0.95 ), 7.595 (1.42), 7.610 (1.61), 7.628 (0.74).

Intermediate 93

tert-Butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-2-methylhexyl]-2-fluorophenyl}ethyl]carbamate (partial mixture of stereoisomers)

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-oxohexyl)-2-fluorophenyl]ethyl}carbamate (Intermediate 92, 297) in THF (8.0 ml) mg, 795 μmol) of magnesium bromido (methyl) (700 μl, 3.4 M, 2.4 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C for 30 minutes and allowed to warm to room temperature overnight. The reaction was cooled back to 0° C. and quenched by addition of aqueous ammonium chloride solution. The mixture was extracted twice with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (300 mg, 95% purity, 60% yield).

LC-MS (Method 2): R _t = 1.40 min; MS (ESIpos): m/z = 407 [M+H]+NH3 ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.834 (1.53), 0.841 (1.59), 0.852 (4.39), 0.859 (2.93), 0.869 (2.28), 0.876 (1.42), 1.116 (3.42) ), 1.132 (3.59), 1.154 (0.68), 1.172 (1.35), 1.190 (1.01), 1.232 (1.31), 1.250 (1.90), 1.267 (5.23), 1.284 (4.60), 1.359 (16.00), 1.4 21 (0.51 ), 1.461 (0.92), 1.482 (0.74), 1.987 (1.03), 2.518 (2.06), 2.523 (1.39), 4.879 (0.48), 4.897 (0.65), 4.915 (0.44), 5.176 (3.63), 5.18 5 (2.26 ), 5.758 (5.62), 7.220 (0.60), 7.239 (1.59), 7.258 (1.29), 7.284 (0.93), 7.299 (1.19), 7.316 (0.51), 7.465 (0.69), 7.480 (1.21), 7.49 7 (0.65 ), 7.528 (0.50), 7.538 (0.62), 7.547 (0.60), 7.558 (0.52).

Intermediate 94

(2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol trifluoroacetic acid salt ( 1/1) (mixture of diastereomers)

tert-butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-2-methylhexyl]-2-fluorophenyl} in dichloromethane (1.0 ml) To a solution of ethyl]carbamate (intermediate 93, 50.0 mg, 128 μmol) was added trifluoroacetic acid (99 μl, 1.3 mmol), and the mixture was stirred at room temperature overnight. Toluene was then added twice to the mixture and the mixture was concentrated. The crude product was used.

LC-MS (Method 2): R _t = 1.14 min; MS (ESIpos): m/z = 290 [M+H] ⁺

intermediate 95

6-bromo-2-methyl-N-{(1RS)-1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine (Racemic)

Using General Method 1, (1RS)-1-[2-(trifluoromethyl)pyridin-4-yl]ethan-1-amine (310 mg, 1.63 mmol) and 6-bromo-2-methylpyri Starting from do[3,4-d]pyrimidin-4-ol (Intermediate 32, 587 mg, 2.45 mmol), 469 mg (95% purity, 66% yield) of the title compound was obtained.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (0.63), 1.169 (1.23), 1.187 (0.59), 1.609 (5.87), 1.627 (5.96), 1.985 (2.66), 2.381 (16.00) ), 2.518 (1.00), 2.522 (0.67), 4.014 (0.55), 4.032 (0.54), 5.556 (0.67), 5.574 (1.04), 5.591 (0.68), 7.747 (1.29), 7.760 (1.33), 7.98 4 (2.58 ), 8.622 (3.74), 8.692 (2.07), 8.704 (1.99), 8.819 (3.71), 8.889 (1.04), 8.906 (1.02).

intermediate 96

6-bromo-2-methyl-N-{(1S*)-1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidine-4- Amine (enantiomer 1)

The enantiomers of intermediate 95 were separated by chiral HPLC:

Analysis method:

Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3 μ, 100x4.6; Eluent A: hexane + 0.1 vol %

diethylamine; Eluent B: Ethanol; Isocratic: 80%A+20%B; Flow rate: 1.4 ml/min; Temperature: 25℃; UV: 280nm

Manufacturing method:

Instrument: PrepCon Labomatic HPLC-2; Column: YMC Cellulose SC 10 μ, 250x50; Eluent A: hexane + 0.1 vol %

diethylamine; Eluent B: Ethanol; Isocratic: 80%A+20%B; Flow rate: 90 ml/min; Temperature: 25℃; UV: 280nm

R _t (Analysis method) Enantiomer 1: 1.66 min.

Intermediate 97

6-bromo-2-methyl-N-{(1R*)-1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidine-4- Amine (enantiomer 2)

The enantiomers of intermediate 95 were separated by chiral HPLC:

Analysis method:

Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3 μ, 100x4.6; Eluent A: hexane + 0.1 vol %

diethylamine; Eluent B: Ethanol; Isocratic: 80%A+20%B; Flow rate: 1.4 ml/min; Temperature: 25℃; UV: 280 nm

Manufacturing method:

Instrument: PrepCon Labomatic HPLC-2; Column: YMC Cellulose SC 10 μ, 250x50; Eluent A: hexane + 0.1 vol %

diethylamine; Eluent B: Ethanol; Isocratic: 80%A+20%B; Flow rate: 90 ml/min; Temperature: 25℃; UV: 280nm

R _t (Analysis method) Enantiomer 1: 2.59 min.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.082 (0.49), 1.258 (0.70), 1.609 (4.88), 1.627 (4.92), 2.382 (16.00), 2.518 (1.19), 2.523 (0.83) ), 5.557 (0.65), 5.575 (1.01), 5.592 (0.65), 7.748 (1.05), 7.761 (1.08), 7.985 (2.13), 8.623 (3.57), 8.692 (1.69), 8.705 (1.63), 8.82 3 (4.02 ), 8.889 (1.00), 8.907 (0.97).

intermediate 98

8-Bromo-6-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one

3-Amino-2-bromo-6-chloro-4-pyridinecarboxylic acid (CAS 1073182-69-0, 67 g, 85% purity, 226.5 mmol) was added to acetic anhydride (700 ml) at room temperature. The reaction was then heated at 100°C for 16 hours. The reaction mixture was concentrated and the residue was used directly in the next step.

intermediate 99

8-Bromo-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol

8-Bromo-6-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one (70 g, 79) in 2-methoxyethanol (700 ml) % purity, 200.8 mmol) and ammonium acetate (Intermediate 98, 61.9 g, 802 mmol) were stirred at 120°C for 16 hours. The reaction mixture was then concentrated and the residue was added to water and stirred at room temperature for 30 minutes. The mixture was filtered and concentrated to give the title compound as a brown solid, which was used directly in the subsequent reaction.

intermediate 100

6-chloro-8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-ol

8-Bromo-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 99, 12 g, 91% purity, 39.7 mmol) and (4-mer) in dimethyl sulfoxide To a solution of toxyphenyl)methanol (11.0 g, 79.6 mmol) was added potassium hydroxide at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The solution was cooled to room temperature, poured into water, and a yellow solid precipitated. The mixture was filtered to obtain a crude solid. The solid was added to a mixture of petroleum ether/ethyl acetate (1:1) and stirred at room temperature for 30 minutes. The mixture was filtered and dried by oil pump under reduced pressure to obtain 6-chloro-8-[(4-methoxybenzyl)oxy]-2-methylpyrido[3,4-d]pyrimidin-4-ol. Obtained as a solid. The solid was added to acetonitrile (70 ml) and recrystallized at 70° C. for 30 minutes. The mixture was filtered and dried under reduced pressure by oil pump to give a brown solid (9.10 g, 90% purity, 62% yield).

LC-MS (Method 1): R _t = 1.08 min; MS (ESIneg): m/z = 330 [MH] ^-

Intermediate 101

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl] -8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-amine

Using General Method 1, (1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethane- 1-amine (intermediate 48, 783 mg, 2.17 mmol) and 6-chloro-8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-ol Starting from (Intermediate 100, 599 mg, 1.80 mmol), the title compound was obtained as a yellow oil (590 mg, 48% yield).

LC-MS (Method 2): R _t = 1.88 min; MS (ESIpos): m/z = 675.6 [M+H] ⁺

Intermediate 102

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-6-( dimethylphosphoryl)-8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-amine

6-chloro-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl] To a solution of -8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-amine (Intermediate 101, 300 mg, 444 μmol), tetrakis( Triphenylphosphine)palladium(0) (77.0 mg, 66.6 μmol) followed by acetonitrile (5 mL), triethylamine (220 μl, 1.6 mmol) and dimethyl-lambda ⁵ -phosphanone (34.7 mg, 444 μmol). was added. The atmosphere was changed to argon, the vial was sealed and heated to 90° C. for 24 hours. The solvent was evaporated and the residue was purified by flash chromatography (silica, dichloromethane, methanol) to give the title compound (208 mg, 65% yield) as a colorless oil.

LC-MS (Method 2): R _t = 1.73 min; MS (ESIpos): m/z = 717.9 [M+H] ⁺

Intermediate 103

6-Bromo-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

5-Amino-2-bromopyridine-4-carboxylic acid (640 mg, 2.95 mmol) and trifluoroethanimidamide (583 mg, 85% purity, 4.42 mmol) in 2-methoxyethanol (9.6 ml) ) was stirred at 130°C (reflux) overnight. The mixture was cooled to room temperature, concentrated and the residue was purified by flash chromatography (silica, dichloromethane, methanol) to give the title compound (809 mg, 99% purity, 93% yield) as a brown solid.

LC-MS (Method 1): R _t = 0.92 min; MS (ESIpos): m/z = 296 [M+H] ⁺

Intermediate 104

6-Bromo-4-chloro-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine

6-Bromo-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 103, 314 mg, 1.07%) in 1,2-dichloroethane (2.9 ml) mmol), 3 drops of DMF thionyl chloride (230 μl, 3.2 mmol) were subsequently added and the mixture was stirred at 100° C. for 3 h. The mixture was then cooled, concentrated and the residue was purified by flash chromatography (silica, dichloromethane, methanol) to give the title compound (311 mg, 94% purity, 88% yield) as a yellow oil.

LC-MS (Method 1): R _t = 1.27 min; MS (ESIpos): m/z = 310.9 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (3.31), 2.523 (2.19), 8.077 (0.65), 8.079 (0.63), 8.188 (15.97), 8.190 (16.00), 9.030 (12.25) ), 9.032 (12.35), 9.063 (0.46), 9.065 (0.44).

Intermediate 105

6-Bromo-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2-(trifluoromethyl)pyrido[3,4-d]pyri Mydin-4-amine

6-Bromo-4-chloro-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine (intermediate 105, 208 mg, 666 μmol) in N,N-dimethylacetamide (2.7 ml) A solution of subsequently added triethylamine (240 μl, 1.7 mmol) and (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethane-1-amine hydrogen chloride (1/1) ( 168 mg, 699 μmol) was added and the mixture was stirred at room temperature overnight. The crude mixture was concentrated and the residue was subjected to flash chromatography (silica, hexane, ethyl acetate) to give the title compound (317 mg, 99% purity, 99% yield) as a dark yellow solid.

LC-MS (Method 1): R _t = 1.55 min; MS (ESIpos): m/z = 481 [M+H] ⁺

Intermediate 106

6-Bromo-2-(difluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

5-Amino-2-bromopyridine-4-carboxylic acid (139 mg, 638 μmol) and difluoroethanimidamide hydrogen chloride (1/1) (100 mg, 766), as described for intermediate 103. It started from.

LC-MS (Method 1): R _t = 0.78 min; MS (ESIpos): m/z = 276 [M+H] ⁺

Intermediate 107

6-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,4-d]pyrimidine

As described for intermediate 104, 6-bromo-2-(difluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 106, 114 mg, 413 μmol) and Starting from thionyl chloride (90 μl, 1.2 mmol), the title compound was obtained.

LC-MS (Method 1): R _t = 1.14 min; MS (ESIpos): m/z = 296 [M+H] ⁺

Intermediate 108

6-bromo-2-(difluoromethyl)-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyri Mydin-4-amine

6-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,4-d]pyrimidine (Intermediate 107, 113 mg, 384 μmol) in N,N-dimethylacetamide (1.5 ml) triethylamine (140 μl, 1000 μmol) followed by (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethane-1-amine hydrogen chloride (1/1) (101 mg). , 422 μmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (142 mg, 94% purity, 75% yield) as a white solid.

LC-MS (Method 1): R _t = 1.45 min; MS (ESIpos): m/z = 463 [M+H] ⁺

Intermediate 109

6-Bromopyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione

A mixture of 5-amino-2-bromopyridine-4-carboxylic acid (488 mg, 2.25 mmol) and urea (540 mg, 8.99 mmol) was stirred at 170° C. overnight. It was then cooled, diluted with water and heated at reflux for 40 minutes. After cooling to room temperature, the title compound partially precipitated (214 mg, 58% purity, 23% yield), which was collected by filtration. The filtrate was concentrated and purified by flash chromatography (silica, dichloromethane, methanol) to give another fraction of the title compound (365 mg, 82% purity, 55% yield).

LC-MS (Method 1): R _t = 0.60 min; MS (ESIneg): m/z = 240 [MH] ^-

intermediate 110

6-Bromo-2,4-dichloropyrido[3,4-d]pyrimidine

6-bromopyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (intermediate 109, 210 mg, 868 μmol), phosphoryl trichloride (2.1 ml, 23 mmol), and N A mixture of N-diisopropylethylamine (760 μl, 4.3 mmol) was stirred at 100° C. overnight. Glacial acetic acid was added to the mixture, the resulting mixture was extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated. The crude product was used without purification in the subsequent reaction.

LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m/z = 280 [M+H] ⁺

Intermediate 111

6-bromo-2-chloro-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidin-4-amine

The reaction was carried out with 6-bromo-2,4-dichloropyrido[3,4-d]pyrimidine (Intermediate 110, 120 mg, 430 μmol) and (1R)-1-[2-methyl-3-(trifluorocarbon) Starting from romethyl)phenyl]ethan-1-amine (96.2 mg, 473 μmol), carried out as described for intermediate 108. After purification by flash chromatography (silica, hexane, ethyl acetate), the title compound (120 mg, 94% purity, 59% yield) was obtained as an orange oil.

LC-MS (Method 1): R _t = 1.49 min; MS (ESIpos): m/z = 447 [M+H] ⁺

Intermediate 112

6-chloro-8-[(4-methoxyphenyl)methoxy]-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido [3,4-d]pyrimidin-4-amine

Using General Method 1, 6-chloro-8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 116, 1.01 g, Starting from (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (744 mg, 3.66 mmol), the title compound was obtained.

LC-MS (Method 2): R _t = 1.53 min; MS (ESIpos): m/z = 517.6 [M+H] ⁺

Intermediate 113

tert-Butyl 4-{8-[(4-methoxyphenyl)methoxy]-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl }amino)pyrido[3,4-d]pyrimidin-6-yl}-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate

The reaction was carried out with 6-chloro-8-[(4-methoxyphenyl)methoxy]-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} -Pyrido[3,4-d]pyrimidin-4-amine (intermediate 112, 409 mg, 791 μmol) and tert-butyl 4-oxo-1,4lambda ⁵ -azaphosphinane-1-carboxylate ( Starting from intermediate 52, 208 mg, 949 μmol), carried out as described for intermediate 102, the title compound (105 mg, 19% yield) was obtained as a yellow oil.

LC-MS (Method 2): R _t = 1.47 min; MS (ESIpos): m/z = 701.0 [M+H] ⁺

Intermediate 117

6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidin-4-amine

The title compound (28.77 g, 81) was reacted as described for intermediate 22 using 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 20 g, 83.3 mmol). % yield) was prepared.

LC-MS (Method 2): R _t = 1.40 min; MS (ESIpos): m/z = 425, 427 [M+H] ⁺

Intermediate 118

Ethyl (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroacetate Hydrogen chloride

Reaction was carried out with (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate (Intermediate 30, 4.2 g , 11.62 mmol) was carried out as described for intermediate 28 to give the title compound (2.8 g, 95% purity, 76% yield).

LC-MS (Method 2): R _t = 1.07 min; MS (ESIpos): m/z = 262.3 [M+H] ⁺

intermediate 130

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}carbamate

Ethyl (3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-2-fluorophenyl)(difluoro)acetate (15.1 g, Sodium tetrahydridoborate (3.31 g, 87.6 mmol) was added little by little to the solution (41.7 mmol), and the resulting mixture was stirred at room temperature overnight. Aqueous hydrochloric acid (1 M) was added to the mixture until the solution reached ˜pH6 and the mixture was stirred for 15 minutes. The mixture was then extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was used without purification in the subsequent reaction.

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: 1.116 (0.42), 1.133 (0.81), 1.151 (0.43), 1.243 (0.69), 1.249 (5.05), 1.261 (0.77), 1.267 (10.29) ), 1.285 (5.04), 1.429 (10.00), 1.439 (8.97), 1.451 (7.32), 1.468 (5.81), 1.496 (0.41), 1.861 (0.54), 2.054 (16.00), 3.753 (0.45), 4. 065 (2.36 ), 4.102 (4.56), 4.120 (3.70), 4.138 (4.61), 4.155 (1.17), 5.005 (0.87), 7.179 (1.53), 7.198 (3.18), 7.218 (1.84), 7.405 (1.36), 7.42 3 (1.95 ), 7.442 (0.95), 7.454 (1.47), 7.458 (1.30), 7.473 (2.13), 7.490 (1.15), 7.495 (1.00).

Intermediate 131

2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2,2-difluoroethane-1-ol trifluoroacetic acid (1/1)

tert-Butyl {(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]-ethyl}carbamate (intermediate) in dichloromethane (530 ml) To a solution of 130, 14.3 g, 44.8 mmol) was added trifluoroacetic acid (52 ml, 670 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, then diluted with toluene and concentrated twice to give the crude title compound (17.6 g, 91% purity, quantitative), which was used in the next step without purification.

LC-MS (Method 2): R _t = 0.74 min; MS (ESIpos): m/z = 220 [M+H] ⁺

Intermediate 132

(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethane-1-amine

2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2,2-difluoroethane-1-ol trifluoroacetic acid (270 ml) in dichloromethane (270 ml) at 0°C 1/1) (Intermediate 131, 17.6 g, 91% purity, 48.1 mmol) was added to a solution of 2,6-dimethylpyridine (39 ml) followed by tert-butyl(dimethyl)silyl trifluoromethanesulfonate (44 ml, 190 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aqueous sodium bicarbonate solution and the organic phase was separated, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (9.09 g, 60% yield) as a yellow oil.

LC-MS (Method 2): R _t = 1.50 min; MS (ESIpos): m/z = 335 [M+H] ⁺

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: -0.008 (3.80), 0.787 (0.44), 0.791 (0.79), 0.799 (16.00), 0.806 (0.60), 1.414 (1.58), 1.430 ( 1.56), 4.108 (0.68), 4.111 (0.66).

Intermediate 133

tert-butyl [(1R)-1-{3-[1,1-difluoro-2-hydroxy( ^2H ₂ )ethyl]-2-fluorophenyl}ethyl]carbamate

The reaction was carried out as described for intermediate 141 using sodium tetradeuterioborate (982 mg, 23.5 mmol) to give the title compound (2.79 g, 92% yield).

LC-MS (Method 2): R _t = 1.26 min; MS (ESIpos): m/z = 339.4 [M+H ₂ O+H] ⁺

Intermediate 134

6-Bromo-N-[(1R)-1-{3-[2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoro( ^2H ₂ )ethyl]-2- fluorophenyl}ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine

Intermediate 134 was prepared in two steps, starting from deuterated intermediate 133, as described for isotopic intermediate 117. The title compound was obtained as a yellow solid (741 mg, 66% yield).

LC-MS (Method 2): R _t = 1.67 min; MS (ESIpos): m/z = 557.5 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm -0.14 - -0.07 (m, 6 H) 0.68 (s, 9 H) 1.55 - 1.64 (m, 3 H) 2.38 (s, 3 H) 5.64 - 5.80 (m, 1 H) 7.22 - 7.31 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.59 - 7.72 (m, 1 H) 8.64 - 8.68 (m, 1 H) 8.79 - 8.81 (m, 1 H) ) 8.84 - 8.90 (m, 1 H).

Intermediate 135

1-[2 _- methyl-3-(trifluoromethyl)phenyl]( ^2H3 )ethan-1-one

1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-one (2.50 g, 12.4 mmol) in 1,4-dioxane (19 ml) and deuterium oxide (19 ml, 1.0 mol) Pyrrolidine (100 μl, 1.2 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. The mixture was extracted with methyl-tert-butyl ether, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The crude product (2.37 g, 93% yield) was used without purification in the subsequent reaction.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.417 (16.00), 2.421 (15.91), 2.518 (1.50), 2.523 (0.98), 7.499 (1.87), 7.519 (4.13), 7.538 (2.36) ), 7.817 (4.10), 7.837 (3.58), 7.928 (3.82), 7.948 (3.49).

Intermediate 136

6-bromo-2-methyl-N-[(1S)-1-[2-methyl-3-(trifluoromethyl)phenyl]( ^2H4 )ethyl]pyrido[ _3,4 -d]pyri Mydin-4-amine

The title compound was prepared as described for its isotopic intermediate 117 starting from the deuterated intermediate 135 using procedures known in the literature to give the title compound (143 mg, 81% yield).

LC-MS (Method 2): R _t = 1.39 min; MS (ESIpos): m/z = 429 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.66), 1.517 (0.48), 1.986 (1.40), 2.379 (16.00), 2.518 (1.13), 2.523 (0.81), 2.606 (4.93) ), 7.345 (0.56), 7.364 (1.26), 7.383 (0.73), 7.544 (1.32), 7.561 (1.05), 7.746 (1.18), 7.766 (1.06), 8.649 (3.33), 8.651 (3.52), 8.78 5 (3.92 ), 8.787 (4.04), 8.967 (1.85).

Intermediate 137

tert-Butyl 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxyl rate

6-Bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 32, 5.00 g, 95% purity, 19.8 mmol), tert-butyl 4- in acetonitrile (100 ml) Oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate (Intermediate 52, 4.34 g, 19.8 mmol), tetrakis(triphenylphosphine)palladium(0) (3.62 g, 3.96 mmol) and tri A mixture of ethylamine (9.7 ml, 69 mmol) was stirred at 90° C. for 22 hours. The mixture was then cooled, filtered and concentrated to give the title compound (7.63 g, 86% purity, 88% yield), which was used in the next step without purification.

LC-MS (Method 2): R _t = 0.58 min; MS (ESIpos): m/z = 379.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.438 (16.00), 2.074 (2.99), 2.432 (5.35), 2.518 (0.81), 2.523 (0.53), 8.434 (0.71), 8.436 (0.73) ), 8.449 (0.72), 8.451 (0.71), 9.128 (1.42).

Intermediate 138

4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one-hydrogen chloride (1/1)

tert-Butyl 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)-4-oxo-1,4lambda in 1,4-dioxane (15 ml) ⁵ To a solution of amino-azaphosphinane-1-carboxylate (Intermediate 137, 2.50 g, 86% purity, 5.68 mmol) hydrogen chloride in 1,4-dioxane (4 M in 1,4-dioxane, 15 ml) , 85 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The mixture was concentrated and the residue was stirred in methyl-tert-butyl ether (50 ml) at room temperature. The resulting suspension was filtered and the solid was collected to give the title compound (2.34 g, 90% purity, quantitative) as a light brown solid, which was used without purification in the subsequent reaction.

LC-MS (Method 1): R _t = 1.09 min; MS (ESIpos): m/z = 279.5 [M+H] ⁺

Intermediate 139

1-Acetyl-4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

Using General Procedure 7, 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one hydrogen chloride Starting from (1/1) (Intermediate 138, 2.34 g, 7.44 mmol), the title compound (3.46 g, 84% purity, 122% yield) was obtained as a brown solid, which was used in the next reaction without purification.

LC-MS (Method 1): R _t = 0.50 min; MS (ESIneg): m/z = 319.5 [MH] ^-

intermediate 140

6-bromo-2,8-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine-4 -Amine

6-Bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[3,4-d) in DMSO (3.3 ml) ]To a mixture of pyrimidin-4-amine (intermediate 117, 200 mg, 470 μmol) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (140 μl, 940 μmol), and the mixture was stirred at room temperature overnight. The mixture was then diluted with water, extracted with dichloromethane and the organic phase was separated, dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC (silica, hexane, ethyl acetate) to give the title compound (170 mg, 82% yield).

LC-MS (Method 2): R _t = 1.52 min; MS (ESIpos): m/z = 439 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.543 (4.55), 1.560 (4.58), 2.327 (0.48), 2.385 (16.00), 2.518 (1.89), 2.523 (1.30), 2.605 (5.15) ), 2.669 (0.52), 2.702 (11.32), 5.651 (0.67), 5.668 (1.04), 5.686 (0.65), 5.758 (1.26), 7.338 (0.58), 7.357 (1.28), 7.377 (0.74), 7.5 38 (1.38 ), 7.555 (1.11), 7.736 (1.23), 7.755 (1.10), 8.472 (3.27), 8.857 (1.05), 8.874 (1.00).

Intermediate 141

2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 2,2-difluoroethane-1-ol

6-Bromo-N-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)- in dichloromethane (2.0 ml) 2-Fluorophenyl]ethyl}-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 131, 300 mg, 540 μmol) was added to a solution of trifluoroacetic acid (620 μl, 8.1 mmol). ) was added, and the mixture was stirred at room temperature overnight. The mixture was then diluted with toluene and concentrated. The residue was purified by flash chromatography ( ^Biotage® Sfaer Amino, hexane, ethyl acetate) to give the title compound (208 mg, 87% yield).

LC-MS (Method 2): R _t = 1.07 min; MS (ESIpos): m/z = 441 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (1.80), 1.171 (3.55), 1.189 (1.70), 1.586 (4.91), 1.603 (4.85), 1.986 (6.51), 2.332 (0.41) ), 2.395 (16.00), 2.518 (2.20), 2.523 (1.49), 3.358 (1.84), 3.372 (0.44), 3.888 (0.48), 3.903 (0.53), 3.924 (0.95), 3.939 (0.98), 3.9 60 (0.48 ), 3.974 (0.45), 3.998 (0.50), 4.016 (1.48), 4.034 (1.47), 4.052 (0.48), 5.706 (0.66), 5.722 (1.62), 5.727 (1.17), 5.737 (0.77), 5.74 5 (1.26 ), 5.756 (0.78), 5.763 (0.75), 7.241 (0.83), 7.261 (1.87), 7.280 (1.08), 7.411 (0.68), 7.428 (1.09), 7.444 (0.53), 7.630 (0.59), 7.64 8 (1.06 ), 7.665 (0.53), 8.665 (4.08), 8.805 (4.52), 8.868 (1.23), 8.886 (1.17).

Intermediate 142

2-(3-{(1R)-1-[(6-bromo-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl )-2,2-difluoroethane-1-ol

Reaction 2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl )-2,2-difluoroethane-1-ol (intermediate 141, 200 mg, 453 μmol) and carried out as described for intermediate 140. The product (208 mg, quantitative) was used without purification in the subsequent reaction.

LC-MS (Method 2): R _t = 1.21 min; MS (ESIpos): m/z = 455 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.96), 1.171 (2.06), 1.189 (1.00), 1.577 (4.34), 1.594 (4.37), 1.986 (3.33), 2.402 (16.00) ), 2.518 (2.69), 2.523 (2.11), 2.718 (11.43), 3.359 (1.74), 3.385 (0.49), 3.886 (0.48), 3.901 (0.52), 3.922 (0.94), 3.938 (1.00), 3.9 57 (0.45 ), 3.974 (0.45), 4.016 (0.68), 4.034 (0.64), 5.704 (1.16), 5.720 (3.01), 5.736 (2.02), 5.756 (2.21), 7.234 (0.76), 7.254 (1.69), 7.27 3 (0.98 ), 7.404 (0.59), 7.422 (0.93), 7.438 (0.47), 7.613 (0.52), 7.630 (0.91), 7.646 (0.46), 8.481 (3.26), 8.756 (1.11), 8.774 (1.06).

Intermediate 143

2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)- 2,2-difluoroethyl trifluoromethanesulfonate

2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}- in dichloromethane (8.5 ml) 2-Fluorophenyl)-2,2-difluoroethane-1-ol (intermediate 141, 757 mg, 1.72 mmol) in a solution of triethylamine (960 μl, 6.9 mmol) and trifluoromethane at 0°C. Sulfonic anhydride (410 μl, 2.4 mmol) was added and the mixture was stirred at room temperature for 2 hours. Additional trifluoromethanesulfonic anhydride (145 μl) was added and the mixture was stirred at room temperature overnight. The mixture was then diluted with dichloromethane (60 ml), washed with water and the organic phase was separated, filtered through a separatory funnel and concentrated. The residue was subjected to flash chromatography (silica, hexane, ethyl acetate) to give the title compound (577 mg, 80% purity, 47% yield).

LC-MS (Method 2): R _t = 1.43 min; MS (ESIpos): m/z = 573.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (5.16), 1.172 (10.62), 1.189 (5.94), 1.206 (0.47), 1.580 (0.54), 1.597 (3.00), 1.614 (2.64) ), 1.986 (16.00), 2.370 (1.69), 2.381 (8.60), 2.518 (1.73), 2.523 (1.19), 3.999 (1.27), 4.016 (3.86), 4.034 (3.80), 4.052 (1.21), 5.3 66 (0.54 ), 5.404 (0.52), 5.700 (0.44), 5.717 (0.64), 5.735 (0.41), 7.325 (0.52), 7.344 (1.06), 7.364 (0.60), 7.503 (0.67), 7.523 (0.57), 7.73 1 (0.43 ), 7.748 (0.57), 8.664 (2.61), 8.809 (3.33), 8.897 (0.61), 8.913 (0.59).

Intermediate 144

2-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-1H-iso indole-1,3(2H)-dione

(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]- in tetrahydrofuran (50 ml) 2-Benzofuran-1 in a solution of ethane-1-amine (intermediate 132, 750 mg, 2.25 mmol), triethylamine (940 μl, 6.7 mmol) and 4-(dimethylamino)pyridine (54 mg, 0.45 mmol) ,3-dione (400 mg, 2.70 mmol) was added and the mixture was stirred at 80° C. overnight. Acetic anhydride (320 μl, 3.4 mmol) was then added and stirring was continued at 80°C overnight. The mixture was cooled and saturated aqueous sodium bicarbonate was added. The organic phase was separated, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography (silica, hexane, ethyl acetate) to give the title compound (833 mg, 80% yield).

LC-MS (Method 2): R _t = 1.67 min; MS (ESIpos): m/z = 464 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.242 (4.60), -0.173 (4.75), 0.587 (0.83), 0.595 (16.00), 0.602 (0.84), 1.791 (1.45), 1.809 (1.44), 2.518 (0.72), 2.523 (0.49), 4.042 (0.40), 7.347 (0.47), 7.842 (6.00).

Intermediate 145

2-{(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}-1H-isoindole-1,3(2H)-dione

2-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl in dichloromethane (10 ml) ]-Ethyl}-1H-isoindole-1,3(2H)-dione (Intermediate 144, 830 mg, 1.79 mmol) was added to a solution of trifluoroacetic acid (2.8 ml) and the mixture was stirred at room temperature overnight. . The mixture was concentrated, diluted with dichloromethane (2 ml) and stirred for a further 3 hours. The mixture was then diluted with toluene, concentrated and the crude product was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (472 mg, 75% yield).

LC-MS (Method 1): R _t = 1.12 min; MS (ESIpos): m/z = 350 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.791 (9.26), 1.809 (9.13), 2.518 (2.54), 2.523 (1.80), 3.811 (0.72), 3.821 (0.77), 3.847 (1.44) ), 3.858 (1.45), 3.883 (0.74), 3.893 (0.70), 5.658 (1.80), 5.674 (1.09), 5.693 (1.92), 5.711 (1.85), 5.729 (0.53), 5.758 (2.00), 7.31 6 (1.30 ), 7.335 (2.94), 7.355 (1.73), 7.472 (0.96), 7.476 (1.09), 7.493 (1.75), 7.509 (0.84), 7.512 (0.79), 7.792 (0.93), 7.809 (1.71), 7.82 7 (1.36 ), 7.829 (1.47), 7.837 (0.79), 7.842 (2.05), 7.851 (15.68), 7.853 (16.00), 7.857 (6.30), 7.862 (2.01), 7.866 (0.76), 7.872 (0.45), 7. 875 (0.63 ), 7.877 (0.52).

Intermediate 146

2-{(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}-1H-isoindole-1,3(2H)-dione

2-{(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}-1H-isoindole-1 in DMF (8.0 ml) To a solution of 3(2H)-dione (intermediate 145, 470 mg, 1.35 mmol) was added sodium hydride (108 mg, 60% purity, 2.69 mmol) and the mixture was stirred at room temperature for 30 minutes. Iodomethane (420 μl, 6.7 mmol) was then added and stirring continued for 1 hour. Additional iodomethane (420 μl, 6.7 mmol) was added and stirring continued overnight. The mixture was then concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (386 mg, 79% yield).

LC-MS (Method 1): R _t = 1.31 min; MS (ESIpos): m/z = 364 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.789 (5.17), 1.807 (5.22), 2.518 (2.09), 2.523 (1.40), 3.272 (16.00), 3.865 (1.14), 3.900 (2.03) ), 3.935 (0.99), 5.696 (1.03), 5.714 (1.01), 5.758 (1.19), 7.331 (0.71), 7.350 (1.61), 7.370 (0.95), 7.493 (0.60), 7.511 (0.97), 7.52 6 (0.47 ), 7.530 (0.44), 7.808 (0.52), 7.826 (1.23), 7.828 (1.11), 7.837 (0.52), 7.842 (1.47), 7.851 (9.53), 7.852 (9.56), 7.856 (3.87), 7.86 1 (1.16 ).

Intermediate 147

(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethane-1-amine

2-{(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}-1H in THF (5.0 ml) and ethanol (5.0 ml) To a solution of -isoindole-1,3(2H)-dione (intermediate 146, 384 mg, 1.06 mmol) was added hydrazine hydrate (510 μl, 11 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was washed with ethanol. The solid was dissolved in dichloromethane and water, the organic phase was separated, washed with saturated aqueous sodium bicarbonate, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (231 mg, 94% yield).

LC-MS (Method 2): R _t = 0.95 min; MS (ESIpos): m/z = 234 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.037 (0.43), 1.045 (0.86), 1.064 (0.45), 1.236 (16.00), 1.253 (15.56), 1.717 (1.32), 1.725 (0.44) ), 1.914 (0.50), 2.024 (1.31), 2.225 (0.42), 2.518 (3.20), 2.523 (2.21), 3.350 (1.22), 3.908 (3.02), 3.911 (2.99), 3.944 (6.20), 3.94 6 (5.96 ), 3.979 (2.95), 3.982 (2.86), 4.258 (0.86), 4.274 (2.69), 4.291 (2.65), 4.308 (0.83), 7.263 (1.66), 7.282 (4.00), 7.301 (2.53), 7.37 2 (1.44 ), 7.377 (1.60), 7.391 (2.23), 7.395 (2.31), 7.410 (1.11), 7.414 (1.06), 7.741 (1.22), 7.758 (2.18), 7.775 (1.10), 7.778 (1.07).

Intermediate 148

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one hydrogen chloride (1/1) (intermediate 164, 1.20 g, 81% purity, 1.94 mmol) was purified by flash chromatography (Snap NH 55 g, hexane, ethyl Acetate) to give 831 mg (92% yield) of the title compound as the free base.

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 464 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (5.11), 1.590 (5.12), 1.753 (0.44), 1.795 (0.87), 1.835 (0.49), 2.256 (0.52), 2.270 (0.76) ), 2.280 (1.01), 2.292 (0.81), 2.304 (1.02), 2.318 (0.98), 2.323 (1.13), 2.327 (1.47), 2.331 (1.14), 2.336 (0.76), 2.416 (16.00), 2.5 18 (4.05 ), 2.523 (2.72), 2.622 (6.51), 2.665 (0.73), 2.669 (0.99), 2.673 (0.69), 3.008 (0.56), 3.023 (0.89), 3.034 (0.76), 3.056 (0.60), 3.07 0 (1.11 ), 3.102 (0.79), 3.110 (0.77), 3.133 (0.72), 3.140 (0.71), 5.701 (0.80), 5.718 (1.24), 5.736 (0.79), 7.346 (0.74), 7.365 (1.60), 7.38 5 (0.92 ), 7.542 (1.73), 7.559 (1.40), 7.783 (1.55), 7.802 (1.40), 8.948 (1.84), 8.963 (1.83), 9.091 (4.44), 9.329 (1.32), 9.346 (1.27).

Intermediate 149

N-{(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-6-bromo-2-methylpyrido[3,4 -d]pyrimidin-4-amine

To a solution of ammonia (1.9 ml, 7.0 M in methanol, 13 mmol) was added 2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3, A solution of 4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2,2-difluoroethyl trifluoromethanesulfonate (Intermediate 143, 750 mg, 1.31 mmol) was added and the mixture was stirred at 50°C for 2 hours. The mixture was concentrated, diluted with dichloromethane and washed with water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate, ethanol) to give 300 mg (90% purity, 47% yield) of the title compound.

LC-MS (Method 2): R _t = 1.09 min; MS (ESIpos): m/z = 440 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.17), 1.172 (8.19), 1.189 (3.89), 1.586 (3.23), 1.603 (3.18), 1.987 (16.00), 2.213 (0.52) ), 2.393 (10.67), 2.518 (2.96), 2.523 (1.98), 3.186 (0.72), 3.224 (1.39), 3.262 (0.66), 3.999 (1.09), 4.017 (3.32), 4.035 (3.36), 4.0 53 (1.11 ), 5.724 (0.50), 5.741 (0.75), 5.759 (0.48), 7.236 (0.59), 7.255 (1.25), 7.275 (0.70), 7.403 (0.44), 7.421 (0.69), 7.635 (0.67), 8.66 5 (2.63 ), 8.807 (2.93), 8.865 (0.76), 8.883 (0.73).

intermediate 150

N-[2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluoro Phenyl)-2,2-difluoroethyl]methanesulfonamide

N-{(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-6-bro in 1,2-dichloroethane (3.1 ml) In a solution of parent-2-methylpyrido[3,4-d]pyrimidin-4-amine (intermediate 149, 150 mg, 341 μmol), triethylamine (240 μl, 1.7 mmol) and DMAP (420 μg, 3.4 μg) were added. μmol) was followed by the addition of methanesulfonyl chloride (32 μl, 410 μmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water, extracted with dichloromethane and the organic phase was washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium sulfate and concentrated. Crude product (158 mg, 85%)

LC-MS (Method 2): R _t = 1.09 min; MS (ESIpos): m/z = 518 [M+H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.587 (1.92), 1.601 (1.91), 2.398 (5.48), 2.514 (0.66), 2.518 (0.62), 2.522 (0.50), 2.820 (0.56) ), 2.829 (6.29), 2.976 (0.62), 3.212 (0.44), 3.349 (1.07), 3.403 (0.59), 3.901 (16.00), 5.749 (0.46), 7.284 (0.73), 7.300 (0.41), 7.7 81 (0.59 ), 8.671 (1.58), 8.808 (1.20), 8.870 (0.46), 8.884 (0.45).

Intermediate 151

N-[2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluoro phenyl)-2,2-difluoroethyl]acetamide

According to General Procedure 7, N-{(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-6-bromo-2-methyl Starting from pyrido[3,4-d]pyrimidin-4-amine (intermediate 149, 150 mg, 341 μmol), the title compound was obtained (170 mg, 85%).

LC-MS (Method 2): R _t = 1.07 min; MS (ESIpos): m/z = 482 [M+H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.959 (1.07), 1.044 (0.55), 1.058 (0.51), 1.114 (0.47), 1.128 (0.47), 1.157 (0.50), 1.171 (0.73) ), 1.186 (0.54), 1.229 (0.43), 1.484 (0.42), 1.586 (5.06), 1.600 (4.97), 1.788 (16.00), 1.796 (1.45), 1.905 (3.25), 1.986 (0.79), 2.2 15 (3.41 ), 2.218 (0.86), 2.397 (15.68), 2.514 (2.47), 2.518 (2.14), 2.522 (1.70), 3.852 (0.42), 3.869 (0.44), 3.934 (0.44), 5.731 (0.81), 5.7 46 (1.21 ), 5.760 (0.80), 7.236 (0.99), 7.252 (1.96), 7.267 (1.14), 7.385 (0.68), 7.399 (1.09), 7.412 (0.55), 7.632 (0.62), 7.646 (1.06), 7.66 0 (0.55 ), 8.328 (0.69), 8.340 (1.37), 8.353 (0.68), 8.674 (3.98), 8.806 (4.43), 8.863 (1.04), 8.878 (1.04).

Intermediate 152

6-Bromo-N-[(1R)-1-{3-[1,1-difluoro-2-(methylamino)ethyl]-2-fluorophenyl}ethyl]-2-methylpyrido[ 3,4-d]pyrimidin-4-amine

The title compound was reacted with 2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluoro Prepared as described for intermediate 149, starting from phenyl)-2,2-difluoroethyl trifluoromethanesulfonate (Intermediate 143, 570 mg, 994 μmol): 290 mg.

LC-MS (Method 2): R _t = 1.18 min; MS (ESIpos): m/z = 454 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (1.00), 1.069 (0.87), 1.153 (3.66), 1.171 (7.33), 1.189 (3.56), 1.582 (5.32), 1.600 (5.27) ), 1.986 (14.81), 2.249 (12.32), 2.384 (16.00), 2.518 (1.36), 2.523 (0.94), 3.183 (0.73), 3.191 (0.66), 3.221 (1.31), 3.228 (1.32), 3 .258 (0.64 ), 3.266 (0.73), 3.998 (1.08), 4.016 (3.28), 4.034 (3.24), 4.052 (1.04), 5.718 (0.82), 5.736 (1.26), 5.753 (0.80), 7.225 (0.90), 7.24 4 (1.98 ), 7.264 (1.18), 7.398 (0.73), 7.416 (1.19), 7.431 (0.58), 7.607 (0.65), 7.624 (1.16), 7.641 (0.59), 8.667 (4.24), 8.804 (4.09), 8.86 5 (1.24 ), 8.883 (1.21).

Intermediate 153

N-[2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluoro phenyl)-2,2-difluoroethyl]-N-methylmethanesulfonamide

The title compound was reacted with 6-bromo-N-[(1R)-1-{3-[1,1-difluoro-2-(methylamino)ethyl]-2-fluorophenyl}ethyl]-2-methyl Starting from pyrido[3,4-d]pyrimidin-4-amine (intermediate 152, 145 mg, 319 μmol), obtained as described for intermediate 150: 187 mg (95% pure, quantitative).

LC-MS (Method 2): R _t = 1.20 min; MS (ESIpos): m/z = 532 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.578 (1.98), 1.596 (1.96), 2.386 (6.74), 2.518 (1.84), 2.523 (1.32), 2.854 (9.21), 2.956 (0.90) ), 3.350 (0.44), 3.903 (16.00), 5.730 (0.47), 5.758 (0.50), 7.281 (0.79), 7.300 (0.45), 7.454 (0.43), 7.665 (0.43), 8.677 (1.70), 8.8 10 (1.93 ), 8.867 (0.52), 8.884 (0.49).

Intermediate 154

N-[2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluoro phenyl)-2,2-difluoroethyl]-N-methylacetamide

The title compound was reacted with 6-bromo-N-[(1R)-1-{3-[1,1-difluoro-2-(methylamino)ethyl]-2-fluorophenyl}ethyl]-2-methyl Prepared as described for intermediate 151 starting from pyrido[3,4-d]pyrimidin-4-amine (intermediate 152, 145 mg, 319 μmol): 130 mg (95% purity, 78% yield).

LC-MS (Method 2): R _t = 1.16 min; MS (ESIpos): m/z = 496 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (1.30), 1.241 (4.54), 1.256 (6.01), 1.272 (3.08), 1.582 (4.92), 1.590 (4.51), 1.600 (5.16) ), 1.608 (4.27), 1.838 (0.55), 1.912 (10.22), 1.924 (15.66), 1.938 (0.41), 2.216 (1.87), 2.337 (0.83), 2.385 (13.71), 2.391 (16.00), 2.518 (9.91 ), 2.523 (7.14), 2.679 (0.84), 2.838 (7.49), 3.019 (10.10), 3.125 (0.40), 3.136 (0.41), 3.143 (0.44), 4.014 (0.47), 4.056 (0.48), 4.1 14 (0.52 ), 4.130 (0.46), 4.153 (0.75), 4.166 (0.81), 4.183 (0.59), 4.206 (0.51), 4.216 (0.72), 4.258 (0.54), 5.710 (1.04), 5.727 (1.59), 5.74 4 (1.02 ), 5.759 (2.82), 7.223 (0.80), 7.243 (1.77), 7.262 (1.06), 7.287 (0.68), 7.307 (1.48), 7.326 (0.89), 7.379 (0.64), 7.396 (1.00), 7.41 2 (0.52 ), 7.436 (0.56), 7.452 (0.85), 7.469 (0.43), 7.616 (0.56), 7.634 (0.98), 7.649 (0.51), 7.675 (0.48), 7.692 (0.84), 7.710 (0.42), 8.67 9 (6.80 ), 8.809 (4.68), 8.812 (4.06), 8.855 (1.12), 8.873 (1.13), 8.893 (1.00), 8.911 (0.92).

Intermediate 155

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl trifluoromethanesulfonate

The title compound was reacted with 1-acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)- Starting from 2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (Example 42, 320 mg, 614 μmol) to intermediate 143 Obtained as described: 94.0 mg (22% purity, 5% yield).

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 654 [M+H] ⁺

Intermediate 156

1-Acetyl-4-(4-{[(1R)-1-{3-[2-(cyclopropylamino)-1,1-difluoroethyl]-2-fluorophenyl}ethyl]amino}- 2-methylpyrido[3,4-d]pyrimidin-6-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

The title compound was reacted with 2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[ From 3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl trifluoromethanesulfonate (Intermediate 155, 90.0 mg, 138 μmol) Starting as described for intermediate 149, 7.00 mg (95% purity, 9% yield) was obtained.

LC-MS (Method 2): R _t = 0.99 min; MS (ESIpos): m/z = 561.6 [M+H] ⁺

Intermediate 157

tert-Butyl 4-[4-({(1R)-1-[3-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-fluorophenyl]ethyl}amino)- 2-methylpyrido[3,4-d]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate

The title compound was reacted with ethyl (3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl )(difluoro)acetate (intermediate 174, 1.68 g, 3.88 mmol) and tert-butyl 4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate (intermediate 52, 850 mg, 3.88 mmol) ) was prepared as described for intermediate 102 starting from: 1.45 g (80% purity, 48% yield).

LC-MS (Method 2): R _t = 1.22 min; MS (ESIpos): m/z = 622.5 [M+H] ⁺

Intermediate 158

Ethyl difluoro{2-fluoro-3-[(1R)-1-{[2-methyl-6-(4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)pyrido[ 3,4-d]pyrimidin-4-yl]amino}ethyl]phenyl}acetate hydrogen chloride (1/1)

The reaction was carried out with tert-butyl 4-[4-({(1R)-1-[3-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-fluorophenyl]ethyl}amino )-2-methylpyrido[3,4-d]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ -azaphosphinane-1-carboxylate, as described for intermediate 138 It was performed as described.

LC-MS (Method 2): R _t = 1.01 min; MS (ESIpos): m/z = 522.5 [M+H] ⁺

Intermediate 159

Ethyl {3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4-d ]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetate

The title compound was reacted with ethyl difluoro{2-fluoro-3-[(1R)-1-{[2-methyl-6-(4-oxo-1,4lambda ⁵ amino-azaphosphinane) according to General Procedure 7. -4-yl) pyrido [3,4-d] pyrimidin-4-yl] amino } ethyl] phenyl } acetate prepared starting from hydrogen chloride (1/1) (intermediate 158, 1.34 g, 2.40 mmol) 622 mg (80% purity, 37% yield) was obtained.

LC-MS (Method 2): R _t = 1.03 min; MS (ESIpos): m/z = 564.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.034 (0.73), 1.052 (1.52), 1.069 (0.74), 1.085 (1.28), 1.102 (1.28), 1.149 (0.78), 1.170 (3.29) ), 1.187 (6.72), 1.205 (3.21), 1.605 (3.17), 1.623 (3.13), 2.118 (9.00), 2.323 (0.47), 2.327 (0.51), 2.392 (9.43), 2.518 (1.30), 2.52 3 (0.95 ), 3.159 (16.00), 3.172 (14.99), 3.439 (0.43), 3.452 (0.49), 3.895 (0.44), 4.087 (1.27), 4.099 (3.87), 4.113 (3.84), 4.126 (1.23), 4. 320 (0.56 ), 4.323 (0.60), 4.338 (1.53), 4.342 (1.61), 4.347 (0.50), 4.356 (1.55), 4.360 (2.00), 4.373 (0.71), 4.377 (0.48), 5.724 (0.51), 5.74 1 (0.78 ), 5.758 (6.79), 6.939 (0.46), 7.326 (0.56), 7.345 (1.21), 7.365 (0.69), 7.565 (0.48), 7.582 (0.80), 7.730 (0.40), 7.749 (0.73), 9.16 6 (0.71 ), 9.183 (0.67), 9.260 (1.74), 9.267 (1.56), 9.272 (1.37), 9.297 (0.71).

intermediate 160

{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4-d ]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetyl chloride

{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2 in dichloromethane (6.9 ml) at 0°C. -methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetic acid (Example 43, 133 mg, 248 μmol) in ethane Dioyl dichloride (84 μl, 990 μmol), and DMF (0.38 μl) were added and the mixture was stirred at room temperature for 2 hours. The acid chloride solution was used directly in the subsequent reaction.

Intermediate 161

Ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl }(difluoro)acetate

The reaction was carried out according to General Procedure 1 with 6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-ol (intermediate 71, 172 mg, 725 μmol) and ethyl {3-[( 1R)-1-Aminoethyl]-2-fluorophenyl}(difluoro)acetate Starting from trifluoroacetic acid (1/1) (intermediate 321 mg, 855 μmol), the title compound (417 mg, quantitative ) was obtained.

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 481.5 [M+H] ⁺

Intermediate 162

tert-Butyl [(1R)-1-{3-[1,1-difluoro-2-(methylamino)-2-oxoethyl]-2-fluorophenyl}ethyl]-carbamate

Ethyl (3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-2-fluorophenyl)(difluoro)acetate (935 mg, 2.59 mmol) was added to methylamine (6.5 ml). , 2.0 M in methanol, 13 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was suspended in tert-butylmethyl ether. The solid was filtered and dried to give the title compound (768 mg, 86% yield) as an off-white solid.

LC-MS (Method 1): R _t = 1.08 min; MS (ESIpos): m/z = 364.7 [M+NH ₄ ] ⁺

Intermediate 163

2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2,2-difluoro-N-methylacetamide-hydrogen chloride (1/1)

The reaction was carried out with tert-butyl [(1R)-1-{3-[1,1-difluoro-2-(methylamino)-2-oxoethyl]-2-fluorophenyl}ethyl]carbamate (intermediate 162, 768 mg, 2.22 mmol) was carried out as described for intermediate 138 to give the title compound (600 mg, 96% yield).

LC-MS (Method 2): R _t = 0.74 min; MS (ESIpos): m/z = 247 [M+H] ⁺

Intermediate 164

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one-hydrogen chloride (1/1)

Reaction tert-butyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] Starting from pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ -azaphosphinane-1-carboxylate (intermediate 187, 400 mg, 710 μmol), carry out as described for intermediate 138 and obtain the title Compound (430 mg, 121% yield) was obtained.

LC-MS (Method 2): R _t = 1.10 min; MS (ESIpos): m/z = 464.5 [M+H] ⁺

The intermediates shown in Table 1 were prepared from each pyrimidin-4-ol derivative and each amine according to General Procedure 2.

Intermediates Table 1

The intermediates shown in Table 2 were prepared from each pyrimidin-4-ol derivative and each amine according to general procedure 6.

Intermediates Table 2

The intermediates shown in Table 3 were prepared from each pyrimidin-4-ol derivative and each amine according to General Procedure 1.

Intermediates Table 3

The intermediates shown in Table 4 were prepared from each N-Boc protected derivative and each amine according to general procedure 3.

Intermediates Table 4

The intermediates shown in Table 5 were prepared by hydrogenation from their respective N-benzyl derivatives: N-benzyl compound (1 equiv) was dissolved in ethanol (0.1 M) and Pd/C (10% Pd, 0.9 equiv) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, concentrated and the crude product obtained was used without purification in the subsequent reaction.

Intermediates Table 5

intermediate 240

(2R*)-1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2- Fluorophenyl)-1,1-difluoropropan-2-ol (diastereomer 2)

The title compound was prepared from Intermediate 43 as described for Intermediate 141 to give 351 mg (90% yield).

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 455 [M+H]+

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.131 (3.39), 1.147 (3.45), 1.154 (2.16), 1.171 (3.70), 1.189 (1.77), 1.582 (4.17), 1.600 (4.21) ), 1.986 (5.52), 2.377 (16.00), 2.518 (1.96), 2.523 (1.38), 4.016 (1.11), 4.034 (1.08), 5.578 (2.44), 5.594 (2.37), 5.703 (0.65), 5.7 20 (1.01 ), 5.738 (0.64), 5.756 (2.12), 7.221 (0.70), 7.240 (1.60), 7.259 (0.96), 7.358 (0.51), 7.362 (0.58), 7.380 (0.88), 7.395 (0.44), 7.59 9 (0.49 ), 7.615 (0.86), 7.632 (0.44), 8.666 (3.67), 8.668 (3.68), 8.805 (4.24), 8.875 (1.05), 8.893 (1.00).

Intermediate 241

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-amine

The title compound was purified with intermediate 32 (1.0 g, 4.2 mmol) and (R)-3-amino-α-methyl-5-(trifluoromethyl)benzenemethanamine (CAS 1213552-98-7, 1.2) according to General Procedure 2. g, 5.0 mmol) to give the title compound (1.47 g, 82% yield).

LC-MS (Method 2): Rt = 1.21 min; MS (ESIpos): m/z = 426 [M+H]+

Intermediate 242

tert-Butyl (R)-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamate

N,N-di in a suspension of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride (2.0 g, 9.84 mmol) in dichloromethane (50 ml) Isopropylethylamine (3.43 ml, 19.6 mmol) was added followed by di-tert-butyldicarbonate (2.58 g, 11.8 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was dried, concentrated and the residue was redissolved in ethanol, imidazole (335 mg) was added and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was dried, concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (2.78 g, 92% yield).

¹ H NMR (400 MHz, chloroform-d) δ ppm 1.40 (br s, 12 H) 2.46 (s, 3 H) 4.70 - 5.26 (m, 2 H) 7.20 - 7.34 (m, 1 H) 7.39 - 7.57 ( m, 2 H).

Intermediate 243

tert-Butyl (R)-(1-(5-bromo-2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamate

Bis(1,5-cyclooctadiene)dimethoxydiiridium (49 mg, 74 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (39) in tetrahydrofuran (15 ml) mg, 148 μmol) of tert-butyl (R)-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamate (Intermediate 242, 1.5 g, 4.95 mmol) and bis. (Pinacolato)diboron (1.26 g, 4.95 mmol) was added and the mixture was stirred at 80° C. for 20 hours. The mixture was then concentrated and the residue was redissolved in methanol (60 ml). Copper (II) bromide (3.31 g, 14.8 mmol) in water (60 ml) was then added to the mixture and the resulting mixture was heated at 90° C. for 6 hours. The mixture was then cooled, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried and concentrated to give the title compound (1.31 g, 69% yield).

LC-MS (Method 2): R _t = 1.51 min; MS (ESIneg): m/z = 380 [MH] ^-

intermediate 244

tert-Butyl (R)-(1-(2,5-dimethyl-3-(trifluoromethyl)phenyl)ethyl)carbamate

tert-Butyl (R)-(1-(5-bromo-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-carbamate (crude intermediate 243, 300 mg, 784 μmol), cesium carbonate A mixture of (511 mg, 1.57 mmol), trimethylboroxine (147 mg, 1.18 mmol), and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57.4 mg, 78.5 μmol) was added to 110 Heated at ℃ for 20 hours. The mixture was cooled, concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate) to give the title compound (180 mg, 72% yield).

LC-MS (Method 2): R _t = 1.49 min; MS (ESIneg): m/z = 316 [MH] ^-

intermediate 245

(R)-1-(2,5-dimethyl-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride

The title compound was reacted with intermediate 28 starting from tert-butyl (R)-(1-(2,5-dimethyl-3-(trifluoromethyl)phenyl)ethyl)carbamate (Intermediate 244, 180 mg, 567 μmol). Prepared as described for the title compound (105 mg, 72% yield).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.41 - 1.53 (m, 3 H) 2.38 (m, 6 H) 4.49 - 4.85 (m, 1 H) 7.44 - 7.59 (m, 1 H) 7.60 - 7.79 (m, 1 H) 8.13 - 8.66 (m, 3 H).

Example 1

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine- 4-amine

6-chloro-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyri in acetonitrile (800 μl) under argon, according to General Procedure 1. in a solution of do[3,4-d]pyrimidin-4-amine (60.0 mg, 158 μmol), dimethyl-lambda ⁵ -phosphanone (12.3 mg, 158 μmol) and triethylamine (77 μl, 550 μmol) Tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 31.5 μmol) was added and the mixture was heated at 90° C. overnight. The mixture was filtered, concentrated and purified by HPLC (basic method) to give the title compound (17 mg, 95% purity, 24% yield).

LC-MS (Method 2): Rt = 1.17 min; MS (ESIneg): m/z = 421 [M-H]-

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]= 1.58 (d, 3H), 1.68 - 1.73 (m, 6H), 2.42 (s, 3H), 2.63 (s, 3H), 5.72 (t , 1H), 7.37 (t, 1H), 7.55 (d, 1H), 7.81 (d, 1H), 8.96 (dd, 1H), 9.07 (s, 1H), 9.38 (d, 1H).

Example 2

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine -4-amine

6-chloro-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[3,4) in acetonitrile (970 μl) under argon. -d] tetrakis(triphenyl) in a solution of pyrimidin-4-amine (70.0 mg, 191 μmol), dimethyl-lambda ⁵ -phosphanone (14.9 mg, 191 μmol) and triethylamine (93 μl, 670 μmol). Phosphine)palladium(0) (35.0 mg, 38.2 μmol) was added and the mixture was heated at 90° C. overnight. The mixture was filtered, concentrated and purified by HPLC (basic method). Fractions containing the title compound were concentrated and further purified by preparative thin layer chromatography (silica gel, CH2Cl2/EtOH 95:5) to give the title compound as a white solid (35 mg, 95% purity, 43% yield). Obtained.

LC-MS (Method 2): Rt = 1.01 min; MS (ESIneg): m/z = 407 [M-H]-

1H NMR (DMSO-d6) δ: 9.30 (d, J=7.4 Hz, 1H), 9.09 (s, 1H), 8.96 (d, J=6.1 Hz, 1H), 7.71 (s, 1H), 7.42-7.57 (m, 1H), 7.09-7.39 (m, 2H), 5.70-5.87 (m, 1H), 2.43 (s, 3H), 1.67-1.75 (m, 6H), 1.59-1.65 (m, 3H)

Example 3

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]- in dichloromethane In a solution of 6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (107 mg, 184 μmol) and triethylsilane (2.9 μl, 18 μmol), trifluoride Roacetic acid (210 μl, 2.8 mmol) was added dropwise at room temperature and the mixture was stirred overnight. Additional trifluoroacetic acid (210 μl, 2.8 mmol) was then added and the reaction mixture was stirred again overnight, then the mixture was diluted with toluene, concentrated and purified by preparative HPLC (acidic method) to give the title compound. (16 mg, 98% purity, 18% yield) was obtained.

LC-MS (Method 4): Rt = 0.82 min; MS (ESIpos): m/z = 467.46 [M+H]+

1H NMR (DMSO-d6) δ: 9.21-9.35 (m, 1H), 9.09 (s, 1H), 8.98 (d, J=6.6 Hz, 1H), 7.54-7.73 (m, 1H), 7.30-7.40 ( m, 1H), 7.14-7.26 (m, 1H), 5.71-5.85 (m, 1H), 5.34 (s, 1H), 2.39-2.43 (m, 3H), 1.68-1.75 (m, 6H), 1.57- 1.63 (m, 3H), 1.18-1.25 (m, 7H)

Example 4

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl in acetonitrile (1.8 ml) under argon. }-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (80.0 mg, 170 μmol), 1 lambda ⁵ -phospholan-1-one (17.7 mg, 170 μmol) and tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 25.6 μmol; CAS-RN:[ 14221-01-3]) was added and the mixture was stirred at 90° C. overnight. The mixture was cooled, filtered and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane, ethanol 9:1) to give the title compound (60.7 mg, 95% purity, 69% yield).

LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 493 [M+H]+

1H NMR (DMSO-d6) δ: 9.32 (d, J=7.4 Hz, 1H), 9.07-9.12 (m, 1H), 9.00-9.06 (m, 1H), 7.59-7.67 (m, 1H), 7.27- 7.36 (m, 1H), 7.18-7.26 (m, 1H), 5.76-5.86 (m, 1H), 5.27-5.39 (m, 1H), 2.41 (s, 3H), 1.93-2.21 (m, 6H), 1.75-1.90 (m, 2H), 1.53-1.63 (m, 3H), 1.12-1.32 (m, 6H)

Example 5

1-benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

Substrate 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3, 4-d]pyrimidin-4-amine (100 mg, 235 μmol), 1-benzyl-1,4lambda ⁵ -azaphosphinan-4-one (49.2 mg, 235 μmol) and triethylamine (110 μl, Tetrakis(triphenylphosphine)palladium(0) (43.1 mg, 47.0 μmol) was added to the solution (820 μmol) and the mixture was heated at 90° C. overnight. The mixture was then cooled, filtered, concentrated and purified by HPLC (basic method) to give the title compound as a white solid (71 mg, 95% purity, 52% yield).

LC-MS (Method 2): Rt = 1.39 min; MS (ESIpos): m/z = 554 [M+H]+

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.566 (5.04), 1.584 (5.07), 1.867 (0.43), 1.906 (0.85), 1.947 (0.48), 2.322 (0.81), 2.326 (1.14) ), 2.332 (0.91), 2.336 (0.67), 2.361 (0.78), 2.372 (0.71), 2.381 (0.76), 2.418 (16.00), 2.518 (3.76), 2.522 (2.40), 2.620 (6.37), 2.6 64 (0.64 ), 2.669 (0.90), 2.673 (0.64), 2.801 (0.93), 2.831 (1.02), 2.860 (0.40), 2.917 (0.62), 2.931 (0.48), 2.950 (0.47), 2.961 (0.54), 2.97 2 (0.66 ), 2.985 (0.47), 3.003 (0.41), 3.655 (6.52), 5.698 (0.78), 5.715 (1.21), 5.733 (0.76), 7.249 (0.50), 7.255 (0.66), 7.263 (1.07), 7.26 8 (0.78 ), 7.271 (0.85), 7.277 (0.91), 7.284 (0.72), 7.323 (0.79), 7.329 (0.48), 7.343 (5.16), 7.350 (5.04), 7.358 (12.53), 7.371 (0.67), 7.3 80 (0.98 ), 7.538 (1.74), 7.556 (1.40), 7.779 (1.54), 7.798 (1.38), 8.977 (1.78), 8.992 (1.74), 9.104 (4.69), 9.350 (1.33), 9.368 (1.28).

Example 6

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3 in ethanol (2.0 ml) ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (130 mg, 235 μmol) was added to Pd/C 10% (50.0 mg, 47.0 μmol). did. The flask was evacuated and refilled with argon (3x). The flask was then purged with hydrogen and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 days. The mixture was then filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane/ethanol). The combined fractions were concentrated to give 35.0 mg (32% yield) of the title compound.

LC-MS (Method 2): R _t = 1.10 min; MS (ESIneg): m/z = 462 [MH] ^-

1H NMR (DMSO-d6) δ: 9.28-9.43 (m, 1H), 9.09 (s, 1H), 8.89-9.01 (m, 1H), 7.74-7.87 (m, 1H), 7.48-7.60 (m, 1H) ), 7.26-7.44 (m, 1H), 5.61-5.84 (m, 1H), 2.96-3.23 (m, 5H), 2.62 (s, 3H), 2.42 (s, 3H), 2.27-2.37 (m, 3H) ), 1.75-1.88 (m, 2H), 1.54-1.62 (m, 3H)

Example 7

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (33.0 mg, 71% purity, 50.2 μmol) was added to a solution of N,N-diisopropylethylamine (10 μl, 60 μmol) and acetic anhydride (5.2 μl, 55 μmol) were added and the mixture was stirred at room temperature overnight. The mixture was then triturated with toluene, concentrated and purified by HPLC (basic method) to give the title compound (21.5 mg, 95% purity, 80% yield).

LC-MS (Method 2): R _t = 1.13 min; MS (ESIneg): m/z = 504 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.574 (4.69), 1.591 (4.67), 2.054 (0.40), 2.116 (16.00), 2.254 (0.43), 2.274 (0.40), 2.327 (1.12) ), 2.332 (0.83), 2.382 (0.42), 2.420 (12.71), 2.518 (4.41), 2.523 (3.04), 2.623 (6.24), 2.669 (1.14), 2.673 (0.82), 3.859 (0.59), 3.8 72 (0.59 ), 3.885 (0.49), 3.916 (0.41), 5.708 (0.48), 5.724 (0.68), 5.739 (0.45), 7.348 (0.72), 7.367 (1.57), 7.387 (0.90), 7.543 (1.68), 7.56 1 (1.36 ), 7.787 (1.50), 7.806 (1.35), 9.010 (1.53), 9.026 (1.52), 9.094 (3.72), 9.375 (0.88), 9.389 (0.84).

Example 8

1-benzyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

6-Bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2- in acetonitrile (3.6 mL) under argon, according to General Procedure 1. Methylpyrido[3,4-d]pyrimidin-4-amine (300 mg, 730 μmol), 1-benzyl-1,4lambda ⁵ amino-azaphosphinan-4-one (153 mg, 730 μmol) and Tetrakis(triphenylphosphine)palladium(0) (126 mg, 109 μmol) was added to a solution of triethylamine (360 μl, 2.6 mmol), and the mixture was heated at 90° C. for 16 hours. The mixture was filtered, concentrated and purified by Biotage-Select flash column chromatography using CH2Cl2/ethanol (9/1) as eluent to give the title compound 1-benzyl-4-[4-({(1R)- 1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -aza Phosphinan-4-one (366 mg, 95% purity, 88% yield) was obtained.

LC-MS (Method 2): R _t = 1.28 min; MS (ESIpos): m/z = 541 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.64), 1.052 (1.44), 1.070 (0.77), 1.234 (0.73), 1.611 (5.60), 1.629 (5.58), 1.870 (0.47) ), 1.914 (0.90), 1.951 (0.54), 2.323 (0.48), 2.327 (0.73), 2.332 (0.69), 2.370 (0.86), 2.380 (0.76), 2.390 (0.84), 2.401 (0.82), 2.43 0 (16.00 ), 2.518 (2.19), 2.523 (1.64), 2.665 (0.45), 2.669 (0.64), 2.673 (0.44), 2.803 (0.98), 2.834 (1.09), 2.860 (0.46), 2.911 (0.69), 2.92 5 (0.54 ), 2.943 (0.54), 2.954 (0.60), 2.965 (0.71), 2.980 (0.52), 2.997 (0.45), 3.654 (6.72), 4.356 (0.44), 5.758 (0.41), 5.774 (0.88), 5.79 2 (1.35 ), 5.810 (0.87), 7.102 (1.35), 7.238 (2.86), 7.249 (0.59), 7.255 (0.73), 7.263 (1.15), 7.271 (0.92), 7.278 (1.74), 7.284 (0.89), 7.29 8 (2.23 ), 7.309 (0.68), 7.317 (1.36), 7.323 (1.06), 7.329 (0.56), 7.343 (4.87), 7.350 (5.10), 7.358 (12.04), 7.374 (1.47), 7.493 (0.73), 7.5 10 (1.23 ), 7.528 (0.61), 7.681 (0.67), 7.699 (1.20), 7.717 (0.60), 8.979 (1.85), 8.995 (1.85), 9.124 (4.59), 9.262 (1.39), 9.280 (1.36).

Example 9

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1,4 lambda ⁵ amino-azaphosphinan-4-one

1-Benzyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[ Palladium on carbon (10 wt%, 158 mg, 148 μmol) in a solution of 3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (100 mg, 185 μmol) ) was added. The flask was evacuated and refilled with argon (repeated 3 times). The flask was then purged with hydrogen gas and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The crude mixture was then filtered and concentrated under reduced pressure. The compound was purified by Biotage flash column chromatography on silica gel using dichloromethane and ethanol (9/1) as eluents. The title compound was obtained (31.0 mg, 37% yield).

LC-MS (Method 2): R _t = 0.97 min; MS (ESIpos): m/z = 450 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.074 (10.08), 1.094 (0.53), 1.236 (0.48), 1.617 (4.46), 1.635 (4.38), 1.808 (0.72), 1.846 (0.40) ), 1.955 (11.30), 2.169 (0.61), 2.297 (0.66), 2.318 (1.09), 2.323 (1.67), 2.327 (2.15), 2.332 (1.51), 2.336 (0.88), 2.429 (13.03), 2. 518 (6.66 ), 2.523 (4.59), 2.660 (0.56), 2.665 (1.17), 2.669 (1.65), 2.673 (1.17), 2.678 (0.56), 2.781 (10.75), 2.942 (16.00), 3.029 (0.64), 3. 081 (0.80 ), 3.090 (0.72), 3.113 (0.66), 3.122 (0.64), 3.129 (0.61), 3.144 (0.61), 3.153 (0.61), 5.777 (0.69), 5.794 (1.06), 5.812 (0.69), 7.10 5 (1.03 ), 7.240 (2.15), 7.284 (0.80), 7.303 (1.65), 7.322 (0.96), 7.376 (0.90), 7.497 (0.58), 7.514 (0.96), 7.532 (0.48), 7.686 (0.53), 7.70 3 (0.96 ), 7.721 (0.48), 8.954 (1.51), 8.969 (1.51), 9.112 (3.69), 9.242 (1.09), 9.259 (1.06).

Example 10

1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1,4lambda ⁵ -azaphosphinan-4-one (33.0 mg, 73.4 μmol) was dissolved in dichloromethane (0.78 mL) at room temperature. N,N-diisopropylethylamine (15 μl, 88 μmol) was added followed by acetic anhydride (7.6 μl, 81 μmol). The mixture was stirred for 16 hours. Toluene was added and the mixture was partially evaporated. The compound was purified by HPLC (basic method) to give the title compound (23 mg, 95% purity, 61% yield).

LC-MS (Method 2): R _t = 1.00 min; MS (ESIpos): m/z = 492 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.11), 1.352 (0.11), 1.619 (2.10), 1.636 (2.04), 1.908 (0.17), 2.058 (0.22), 2.118 (6.62) ), 2.327 (3.48), 2.331 (2.48), 2.433 (5.63), 2.518 (16.00), 2.523 (10.32), 2.669 (3.42), 2.673 (2.43), 2.678 (1.16), 3.707 (0.17), 3. 866 (0.33 ), 4.037 (0.17), 5.784 (0.28), 5.799 (0.39), 5.817 (0.28), 7.106 (0.50), 7.241 (0.99), 7.287 (0.33), 7.306 (0.77), 7.325 (0.44), 7.37 7 (0.44 ), 7.500 (0.33), 7.516 (0.50), 7.534 (0.22), 7.688 (0.28), 7.706 (0.50), 7.725 (0.22), 9.014 (0.72), 9.031 (0.77), 9.118 (1.82), 9.28 2 (0.55 ), 9.300 (0.50).

Example 11

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-6-( Dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-amine (100 mg, 168 μmol) was dissolved in dichloromethane (2 mL) at room temperature. Triethylsilane (2.7 μl, 17 μmol) was added followed by trifluoroacetic acid (190 μl, 2.5 mmol). The resulting mixture was stirred at room temperature for 20 hours. Water and ethyl acetate were added to the mixture and the phases were separated. The organic phase was dried through hydrophobic filtration. The solvent was evaporated. The compound was purified by HPLC (basic method) followed by preparative thin layer chromatography using dichloromethane and ethanol as eluents to give the title compound (12.0 mg, 15% yield).

LC-MS (Method 2): R _t = 1.12 min; MS (ESIpos): m/z = 481 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (6.15), 1.229 (6.43), 1.582 (4.64), 1.599 (4.66), 1.671 (6.95), 1.674 (7.40), 1.705 (7.13) ), 1.708 (7.21), 2.416 (16.00), 2.518 (0.97), 2.523 (0.64), 2.770 (13.42), 5.335 (7.89), 5.757 (3.57), 5.768 (0.76), 5.786 (1.17), 5. 803 (0.74 ), 7.195 (0.74), 7.214 (1.75), 7.233 (1.13), 7.291 (0.66), 7.295 (0.77), 7.312 (1.09), 7.328 (0.51), 7.332 (0.47), 7.601 (0.61), 7.61 7 (1.06 ), 7.633 (0.55), 8.794 (1.93), 8.810 (1.91), 9.162 (1.32), 9.181 (1.26).

Example 12

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

According to General Procedure 1, 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2 -Fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (80.0 mg, 170 μmol) was reacted with diisopropylphosphine oxide (22.9 mg, 170 μmol) at 90°C for 16 hours. I ordered it. Afterwards, additional tetrakis(triphenylphosphine)palladium(0) (19.7 mg, 17.0 μmol) was added and the mixture was stirred at 90° C. for a further 16 hours. The mixture was then cooled to room temperature and filtered. The compound was purified by preparative thin layer chromatography on silica gel plates using dichloromethane and ethanol as solvents to give the title compound (20.1 mg, 95% purity, 21% yield).

LC-MS (Method 2): R _t = 1.19 min; MS (ESIpos): m/z = 523 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.922 (3.58), 0.929 (3.65), 0.939 (3.78), 0.947 (3.71), 0.960 (3.71), 0.968 (3.78), 0.978 (3.71) ), 0.986 (3.51), 1.052 (0.95), 1.065 (0.95), 1.070 (1.01), 1.083 (0.95), 1.097 (1.22), 1.105 (3.78), 1.115 (4.25), 1.123 (4.25), 1.13 3 (3.71 ), 1.143 (3.65), 1.153 (3.71), 1.161 (3.71), 1.171 (3.51), 1.195 (6.82), 1.222 (7.02), 1.593 (4.86), 1.611 (4.86), 2.318 (0.47), 2.40 9 (16.00) ), 2.426 (0.88), 2.444 (1.35), 2.452 (1.15), 2.461 (1.82), 2.470 (2.30), 2.518 (6.75), 2.523 (4.66), 3.378 (0.41), 5.333 (2.23), 5.75 8 (9.92 ), 5.769 (0.88), 5.787 (1.28), 5.805 (0.81), 7.211 (0.74), 7.230 (1.82), 7.249 (1.22), 7.300 (0.88), 7.317 (1.22), 7.333 (0.54), 7.61 8 (0.68 ), 7.634 (1.15), 7.650 (0.61), 8.898 (1.96), 8.912 (1.89), 9.079 (4.86), 9.081 (4.79), 9.357 (1.42), 9.375 (1.35).

Example 13

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidine- 4-amine

Following General Procedure 1: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d] From pyrimidin-4-amine (60.0 mg, 141 μmol) and dimethylphosphine oxide (11.0 mg, 141 μmol), the title compound (25.1) was obtained after purification by preparative TLC (CH ₂ Cl ₂ /EtOH 8:1). mg, 40%) was obtained.

LC-MS (Method 2): R _t = 1.08 min; MS (ESIpos): m/z = 423 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.565 (4.57), 1.583 (4.65), 1.782 (14.54), 1.815 (13.99), 2.399 (16.00), 2.518 (3.22), 2.522 (2.15) ), 2.623 (5.45), 2.673 (0.50), 5.713 (0.69), 5.730 (1.07), 5.748 (0.69), 7.346 (0.63), 7.366 (1.38), 7.385 (0.80), 7.542 (1.46), 7.56 0 (1.18 ), 7.784 (1.29), 7.803 (1.18), 9.175 (1.57), 9.180 (1.76), 9.186 (1.60), 9.192 (1.73), 9.230 (1.13), 9.244 (1.98), 9.249 (2.01), 9.27 4 (1.46 ), 9.279 (1.24).

Example 14

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol

According to General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2 From -fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (60.0 mg, 128 μmol) and dimethylphosphine oxide (9.98 mg, 128 μmol), preparative HPLC (basic method) The title compound (30.0 mg, 48%) was obtained after purification by ).

LC-MS (Method 5): R _t = 0.87 min; MS (ESIpos): m/z = 467 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.205 (5.76), 1.230 (6.07), 1.588 (4.46), 1.606 (4.51), 1.786 (8.48), 1.819 (8.44), 2.396 (16.00) ), 2.518 (8.50), 2.523 (6.25), 5.340 (6.99), 5.782 (0.71), 5.800 (1.11), 5.817 (0.72), 7.206 (0.69), 7.225 (1.64), 7.244 (1.08), 7.30 6 (0.72 ), 7.323 (1.03), 7.338 (0.50), 7.606 (0.55), 7.622 (0.99), 7.637 (0.53), 9.125 (1.22), 9.143 (1.18), 9.188 (1.57), 9.193 (1.97), 9.20 0 (1.71 ), 9.205 (1.81), 9.250 (1.44), 9.255 (1.28), 9.280 (1.41), 9.285 (1.28).

Example 15

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[2,3-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

According to General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2 -Fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (100 mg, 213 μmol), di(propan-2-yl)-lambda ⁵ -phosphanone (28.6 mg, 213 μmol) ) and tetrakis(triphenylphosphine)palladium(0) (61.5 mg, 53.3 μmol) were heated at 90°C for 2 days. The title compound (52.6 mg, 45%) was obtained after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 1.04 min; MS (ESIneg): m/z = 521 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.925 (3.35), 0.928 (3.47), 0.942 (3.57), 0.946 (3.47), 0.965 (3.47), 0.969 (3.52), 0.982 (3.54) ), 0.987 (3.37), 1.088 (2.86), 1.103 (3.69), 1.106 (3.84), 1.120 (3.32), 1.126 (3.30), 1.141 (3.76), 1.143 (3.84), 1.158 (2.93), 1.19 3 (5.98 ), 1.219 (6.16), 1.600 (4.45), 1.617 (4.40), 2.397 (16.00), 2.518 (3.84), 2.523 (2.49), 5.335 (4.35), 5.758 (1.91), 5.777 (0.73), 5.7 95 (1.12 ), 5.813 (0.71), 7.210 (0.71), 7.229 (1.71), 7.248 (1.10), 7.299 (0.66), 7.304 (0.76), 7.320 (1.05), 7.336 (0.51), 7.341 (0.44), 7.59 8 (0.59 ), 7.614 (1.03), 7.629 (0.54), 9.073 (1.47), 9.078 (1.91), 9.080 (1.83), 9.085 (1.49), 9.174 (1.27), 9.179 (1.17), 9.199 (1.27), 9.20 4 (1.12 ), 9.241 (1.25), 9.259 (1.20).

Example 16

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

According to General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2 From -fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (100 mg, 213 μmol) and phospholane 1-oxide (22.2 mg, 213 μmol), preparative TLC (CH The title compound (66.6 mg, 60%) was obtained after purification by ₂ Cl ₂ /EtOH 9:1).

LC-MS (Method 2): R _t = 0.95 min; MS (ESIneg): m/z = 491 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.205 (6.62), 1.230 (6.90), 1.591 (5.00), 1.609 (4.97), 1.892 (0.48), 1.910 (0.63), 1.947 (1.32) ), 1.973 (1.37), 1.986 (1.06), 2.017 (1.06), 2.037 (0.99), 2.059 (0.91), 2.077 (0.58), 2.161 (0.48), 2.180 (0.71), 2.195 (0.89), 2.20 9 (0.89 ), 2.223 (0.53), 2.327 (0.91), 2.331 (0.66), 2.397 (16.00), 2.518 (3.65), 2.523 (2.48), 2.669 (0.91), 2.673 (0.63), 5.342 (6.39), 5.7 59 (8.98 ), 5.784 (0.81), 5.802 (1.24), 5.820 (0.79), 7.202 (0.79), 7.221 (1.85), 7.241 (1.19), 7.300 (0.74), 7.305 (0.84), 7.322 (1.17), 7.33 7 (0.58 ), 7.341 (0.53), 7.606 (0.66), 7.622 (1.14), 7.638 (0.61), 9.114 (1.70), 9.119 (1.93), 9.124 (1.80), 9.130 (1.72), 9.177 (1.37), 9.19 5 (1.29 ), 9.243 (1.50), 9.248 (1.37), 9.272 (1.50), 9.277 (1.37).

Example 17

6-(dimethylphosphoryl)-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrido Mydin-4-amine

Following General Procedure 1: 6-bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3- from d]pyrimidin-4-amine (100 mg, 228 μmol), dimethylphosphine oxide (35.5 mg, 455 μmol) and tetrakis(triphenylphosphine)palladium(0) (52.6 mg, 45.5 μmol); The title compound (24.0 mg, 23%) was obtained after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 1.10 min; MS (ESIneg): m/z = 435 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.564 (4.64), 1.582 (4.69), 1.838 (16.00), 1.872 (15.74), 2.336 (0.46), 2.364 (15.23), 2.518 (5.56) ), 2.523 (3.92), 2.613 (5.61), 2.678 (0.44), 2.832 (12.47), 5.705 (0.71), 5.722 (1.08), 5.739 (0.69), 7.342 (0.64), 7.362 (1.39), 7.3 81 (0.80 ), 7.541 (1.51), 7.559 (1.22), 7.765 (1.35), 7.785 (1.20), 8.926 (2.19), 8.958 (2.17), 9.037 (1.17), 9.054 (1.11).

Example 18

N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d] Pyrimidin-4-amine

Following General Procedure 1: 6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3 -d]pyrimidin-4-amine (100 mg, 235 μmol), dimethylphosphine oxide (36.7 mg, 470 μmol) and tetrakis(triphenylphosphine)palladium(0) (54.3 mg, 47.0 μmol) , the title compound (31.0 mg, 30%) was obtained after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 0.96 min; MS (ESIpos): m/z = 423 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.611 (4.86), 1.629 (4.84), 1.839 (13.82), 1.872 (13.83), 2.331 (0.48), 2.376 (16.00), 2.518 (2.60) ), 2.523 (1.81), 2.673 (0.46), 2.845 (13.08), 5.789 (0.74), 5.808 (1.14), 5.825 (0.72), 7.107 (1.09), 7.243 (2.31), 7.280 (0.82), 7.2 99 (1.78 ), 7.319 (1.01), 7.379 (0.96), 7.497 (0.61), 7.514 (1.02), 7.532 (0.50), 7.671 (0.56), 7.688 (1.01), 7.706 (0.50), 8.923 (2.23), 8.95 1 (1.42 ), 8.956 (2.52), 8.969 (1.21).

Example 19

1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

Following General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl} -2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (100 mg, 207 μmol), dimethylphosphine oxide (16.1 mg, 207 μmol) and tetrakis(triphenyl) From phosphine)palladium(0) (59.8 mg, 51.7 μmol), the title compound (40.0 mg, 38%) was obtained after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 0.92 min; MS (ESIneg): m/z = 479 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (0.41), 1.205 (5.87), 1.229 (6.09), 1.588 (4.60), 1.605 (4.60), 1.839 (12.73), 1.873 (12.58) ), 2.074 (0.63), 2.331 (1.63), 2.337 (0.74), 2.363 (16.00), 2.518 (8.76), 2.523 (6.16), 2.669 (2.30), 2.673 (1.56), 2.678 (0.71), 2.8 46 (12.96 ), 5.344 (7.94), 5.779 (0.71), 5.797 (1.11), 5.815 (0.71), 7.202 (0.71), 7.221 (1.67), 7.240 (1.08), 7.305 (0.74), 7.322 (1.04), 7.33 8 (0.48 ), 7.591 (0.56), 7.607 (1.00), 7.624 (0.52), 8.924 (2.30), 8.938 (1.34), 8.957 (3.12).

Example 20

1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7 -Dimethylpyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one

Following General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl} -2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (104 mg, 215 μmol), 1lambda ⁵ amino-phospholan-1-one (22.4 mg, 215 μmol) and tetrakis(triphenylphosphine)palladium(0) (62.2 mg, 53.8 μmol) to give the title compound (23.8 mg, 21%) after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 0.97 min; MS (ESIpos): m/z = 507 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (6.28), 1.226 (6.50), 1.601 (4.85), 1.619 (4.83), 1.797 (0.56), 1.806 (0.53), 1.820 (0.65) ), 1.837 (0.60), 1.847 (0.66), 1.863 (0.47), 1.948 (0.55), 1.968 (0.73), 1.983 (0.78), 2.012 (1.21), 2.047 (0.61), 2.064 (0.56), 2.07 4 (0.50 ), 2.327 (0.80), 2.332 (0.60), 2.366 (16.00), 2.426 (0.47), 2.444 (0.47), 2.518 (3.71), 2.523 (2.54), 2.669 (0.83), 2.673 (0.58), 2.8 28 (13.23 ), 5.344 (5.12), 5.782 (0.76), 5.800 (1.18), 5.817 (0.75), 7.202 (0.75), 7.221 (1.78), 7.240 (1.13), 7.302 (0.66), 7.306 (0.76), 7.32 3 (1.10 ), 7.339 (0.53), 7.343 (0.48), 7.584 (0.61), 7.600 (1.08), 7.616 (0.55), 8.907 (2.08), 8.938 (3.17), 8.956 (1.30).

Example 21

1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl} amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol

Following General Procedure 1: 1-(3-{(1R)-1-[(6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl} -2-Fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (104 mg, 215 μmol), di(propan-2-yl)-lambda ⁵ amino-phosphanone (28.9 mg , 215 μmol) and tetrakis(triphenylphosphine)palladium(0) (99.5 mg, 86.1 μmol) were heated at 90°C for 3 days. The title compound (20.5 mg, 17%) was obtained after purification by preparative TLC (CH ₂ Cl ₂ /EtOH 9:1).

LC-MS (Method 2): R _t = 1.05 min; MS (ESIpos): m/z = 537 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.878 (2.79), 0.894 (3.73), 0.896 (3.80), 0.911 (3.03), 0.918 (3.01), 0.934 (3.75), 0.935 (3.73) ), 0.951 (2.72), 1.021 (0.63), 1.040 (0.76), 1.050 (0.45), 1.052 (0.67), 1.058 (0.83), 1.070 (0.43), 1.077 (1.06), 1.095 (0.61), 1.15 8 (2.76 ), 1.176 (6.18), 1.185 (6.61), 1.193 (5.28), 1.213 (9.15), 1.231 (3.30), 1.608 (4.49), 1.626 (4.45), 2.331 (0.99), 2.337 (0.45), 2.36 7 (16.00) ), 2.518 (5.28), 2.523 (3.75), 2.558 (0.72), 2.567 (1.08), 2.575 (0.99), 2.584 (0.70), 2.593 (0.92), 2.610 (0.52), 2.673 (0.97), 2.67 8 (0.43 ), 2.834 (10.52), 5.331 (6.47), 5.759 (1.84), 5.776 (0.72), 5.794 (1.10), 5.812 (0.70), 7.209 (0.70), 7.229 (1.66), 7.248 (1.12), 7.3 01 (0.65 ), 7.305 (0.76), 7.322 (1.03), 7.338 (0.52), 7.342 (0.45), 7.557 (0.56), 7.573 (1.01), 7.589 (0.52), 8.817 (1.10), 8.844 (1.10), 8.98 8 (1.01 ), 9.006 (0.99).

Example 22

6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[ 2,3-d]pyrimidin-4-amine

According to General Procedure 1: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl) Pyrido[2,3-d]pyrimidin-4-amine (70.0 mg, 142 μmol), dimethylphosphine oxide (15.5 mg, 199 μmol) and tetrakis(triphenylphosphine)palladium(0) (73.8 mg, 63.4 μmol) was heated at 90°C for 2 days. The title compound (10.0 mg, 14%) was obtained after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 1.24 min; MS (ESIpos): m/z = 491 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (4.29), 1.154 (0.53), 1.172 (0.53), 1.232 (0.71), 1.590 (3.65), 1.607 (3.65), 1.861 (3.88) ), 1.895 (3.88), 2.327 (3.41), 2.331 (2.47), 2.430 (11.71), 2.518 (16.00), 2.523 (10.65), 2.618 (4.82), 2.669 (3.53), 2.673 (2.53), 5 .730 (0.59 ), 5.747 (1.00), 5.760 (10.35), 7.353 (0.53), 7.373 (1.12), 7.393 (0.65), 7.556 (1.41), 7.575 (1.18), 7.792 (1.12), 7.811 (1.00), 9.4 63 (1.35 ), 9.495 (1.29), 9.575 (0.59), 9.593 (0.59).

Example 23

(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]- 2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol (mixture of diastereomers)

Using general procedure 6, (2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol Trifluoroacetic acid salt (1/1) (mixture of diastereomers, intermediate 82, 64.0 mg, 81% purity, 128 μmol) and 6-(dimethylphosphoryl)-2-methylpyrido[3,4- Starting from d]pyrimidin-4-ol (33.5 mg, 141 μmol) (intermediate 71). Purification by preparative thin layer chromatography (silica gel plate 20 x 20 cm, dichloromethane, ethanol) gave 15.5 mg (95% purity, 23% yield) of the title compound.

LC-MS (Method 2): R _t = 1.18 min; MS (ESIpos): m/z = 509 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.791 (2.29), 0.802 (3.24), 0.809 (6.54), 0.819 (7.45), 0.827 (3.42), 0.837 (3.37), 1.135 (5.66) ), 1.154 (5.70), 1.176 (1.10), 1.194 (1.96), 1.212 (2.28), 1.228 (2.28), 1.268 (0.77), 1.286 (0.72), 1.299 (0.72), 1.313 (0.68), 1.33 0 (0.80 ), 1.346 (0.74), 1.358 (0.80), 1.376 (0.67), 1.413 (0.60), 1.452 (1.14), 1.465 (0.96), 1.481 (1.10), 1.492 (1.09), 1.516 (0.52), 1.58 6 (6.82 ), 1.603 (6.76), 1.689 (16.00), 1.723 (15.99), 2.084 (0.45), 2.332 (1.50), 2.336 (0.64), 2.411 (14.13), 2.423 (13.61), 2.518 (7.82), 2.523 (5.56 ), 2.673 (1.51), 2.678 (0.64), 5.174 (4.52), 5.191 (4.24), 5.758 (2.39), 5.765 (0.68), 5.782 (1.10), 5.801 (1.02), 5.821 (1.05), 5.83 9 (0.65 ), 7.200 (0.69), 7.207 (0.70), 7.220 (1.69), 7.226 (1.66), 7.239 (1.16), 7.245 (1.08), 7.295 (0.74), 7.312 (1.17), 7.322 (1.09), 7.33 8 (0.52 ), 7.605 (0.90), 7.623 (1.55), 7.641 (0.86), 8.963 (1.72), 8.970 (1.78), 8.979 (1.76), 8.984 (1.75), 9.089 (6.35), 9.263 (1.15), 9.28 2 (2.12 ), 9.301 (1.16).

Example 24

6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 1)

6-bromo-2-methyl-N-{(1S*)-1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidine-4- Add tetrakis(triphenylphosphine)palladium(0) (21.0 mg, 18.2 μmol) to a solution of amine (enantiomer 1) (intermediate 96, 50 mg, 121.3 μmol) followed by acetonitrile (2 mL) and triethylamine. (59 μl, 420 μmol) and dimethyl-lambda ⁵ amino-phosphanone (11 μl, 150 μmol) were added. The atmosphere was changed to argon, the vial was sealed and heated to 90° C. for 24 hours. The solvent was evaporated and the residue was redissolved in DMSO (2.5 mL), filtered, and then HPLC purified (basic method) to give 22.0 mg (98% purity, 43% yield) of the title compound as a white solid.

LC-MS (Method 2): R _t = 1.02 min; MS (ESIpos): m/z = 410.4 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.627 (5.33), 1.645 (5.36), 1.689 (5.99), 1.696 (6.11), 1.723 (6.04), 1.730 (5.97), 2.427 (16.00) ), 2.518 (1.11), 2.522 (0.71), 5.611 (0.73), 5.629 (1.13), 5.647 (0.72), 7.761 (1.25), 7.770 (1.26), 7.773 (1.27), 8.004 (2.54), 8.69 9 (2.00 ), 8.711 (1.95), 8.919 (1.74), 8.920 (1.80), 8.935 (1.80), 8.937 (1.78), 9.108 (4.03), 9.275 (1.20), 9.293 (1.17).

Example 25

6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 2)

6-bromo-2-methyl-N-{(1R*)-1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidine-4- Add tetrakis(triphenylphosphine)palladium(0) (21.0 mg, 18.2 μmol) to a solution of amine (enantiomer 2) (intermediate 97, 50 mg, 121.3 μmol) followed by acetonitrile (2 mL) and triethylamine. (59 μl, 420 μmol) and dimethyl-lambda ⁵ amino-phosphanone (11 μl, 150 μmol) were added. The atmosphere was changed to argon, the vial was sealed and heated to 90° C. for 24 hours. The solvent was evaporated and the residue was redissolved in DMSO (2.5 mL), filtered, and then HPLC purified (basic method) to give 17.0 mg (98% purity, 34% yield) of the title compound as a white solid.

LC-MS (Method 2): R _t = 1.01 min; MS (ESIpos): m/z = 410.4 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.61 - 1.66 (m, 3 H) 1.68 - 1.71 (m, 3 H) 1.71 - 1.75 (m, 3 H) 2.41 - 2.45 (m, 3 H) 5.43 - 5.74 (m, 1 H) 7.69 - 7.84 (m, 1 H) 7.95 - 8.13 (m, 1 H) 8.61 - 8.77 (m, 1 H) 8.85 - 9.00 (m, 1 H) 9.04 - 9.18 (m, 1 H) 9.24 - 9.39 (m, 1 H)

Example 26

4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-6-(dimethylphosphoryl )-2-methylpyrido[3,4-d]pyrimidin-8-ol

N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl in dichloromethane (3.0 ml) ) Ethyl]-6-(dimethylphosphoryl)-8-[(4-methoxyphenyl)methoxy]-2-methylpyrido[3,4-d]pyrimidin-4-amine (Intermediate 102, 208 mg , 290 μmol), trifluoroacetic acid (3.0 ml) was slowly added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified using preparative HPLC (Instrument: Waters Autopurificationsystem; Column: %); Eluent B: Acetonitrile; Gradient: 0.0-0.5 min 9% B (35-70 ml/min), 0.5-5.5 min 9-29% B; Flow: 70 ml/min; Temperature: RT; DAD scan : 210-400 nm) to give the title compound (52 mg, 99% purity, 37% yield) as a white solid.

LC-MS (Method 2): R _t = 0.75 min; MS (ESIpos): m/z = 483.7 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.17 - 1.27 (m, 6 H) 1.50 - 1.61 (m, 3 H) 1.69 - 1.82 (m, 6 H) 2.34 (s, 3 H) 5.21 - 5.44 (m, 1 H) 5.63 - 5.79 (m, 1 H) 7.16 - 7.25 (m, 1 H) 7.27 - 7.34 (m, 1 H) 7.47 - 7.71 (m, 2 H) 8.72 (d, J=7.35 Hz , 1 H) 11.22 - 12.25 (m, 1 H)

Example 30

1-Acetyl-4-[8-hydroxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

Following General Procedure 3, tert-butyl 4-{8-[(4-methoxyphenyl)methoxy]-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluorocarbon Romethyl)phenyl]ethyl}amino)-pyrido[3,4-d]pyrimidin-6-yl}-4-oxo-1,4lambda ⁵ -azaphosphinane-1-carboxylate (Intermediate 113, Starting from 105 mg, 150 μmol), the title compound (10.0 mg, 98% purity, 13% yield) was obtained as a white solid after purification by preparative HPLC (basic method).

LC-MS (Method 2): R _t = 0.74 min; MS (ESIpos): m/z = 522 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.42), 1.232 (1.72), 1.315 (0.43), 1.527 (5.25), 1.545 (5.24), 1.844 (1.36), 1.850 (0.63) ), 1.870 (0.57), 1.908 (0.56), 2.074 (1.44), 2.101 (16.00), 2.259 (0.44), 2.291 (0.60), 2.318 (1.17), 2.323 (2.23), 2.327 (3.04), 2.3 31 (2.40 ), 2.344 (14.10), 2.518 (9.95), 2.523 (6.86), 2.603 (7.23), 2.660 (0.81), 2.665 (1.84), 2.669 (2.56), 2.673 (1.79), 2.678 (0.81), 3.2 34 (0.52 ), 3.262 (0.63), 3.659 (0.47), 3.685 (0.49), 5.616 (0.60), 5.633 (0.87), 5.646 (0.57), 6.549 (0.51), 7.339 (0.80), 7.358 (1.78), 7.37 7 (1.06 ), 7.529 (1.97), 7.547 (1.61), 7.602 (0.56), 7.625 (0.54), 7.768 (1.72), 7.787 (1.56), 8.850 (0.80).

Example 31

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carbaldehyde

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-pyrido[3,4- d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (intermediate 148, 50.0 mg, 108 μmol) was added to a solution of potassium carbonate (14.9 mg, 108 μmol) and ethyl formate ( 70 μl, 860 μmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, filtered and concentrated. The residue was purified by preparative TLC (silica, dichloromethane, ethanol) to give the title compound (29.1 mg, 95% purity, 52% yield).

LC-MS (Method 2): R _t = 1.11 min; MS (ESIpos): m/z = 492 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.49), 1.575 (6.11), 1.593 (6.07), 1.955 (0.63), 2.061 (0.66), 2.100 (0.40), 2.258 (0.71) ), 2.281 (0.61), 2.361 (0.53), 2.374 (0.79), 2.396 (0.85), 2.422 (16.00), 2.623 (8.90), 3.659 (0.64), 3.694 (0.68), 3.774 (0.57), 3.7 85 (0.57 ), 3.808 (1.03), 3.821 (1.02), 3.834 (0.80), 3.867 (0.70), 3.879 (0.41), 3.939 (0.43), 3.974 (0.61), 3.987 (0.61), 5.707 (0.89), 5.72 3 (1.34 ), 5.741 (0.88), 7.349 (0.96), 7.368 (2.03), 7.388 (1.19), 7.544 (2.27), 7.563 (1.86), 7.786 (2.04), 7.806 (1.85), 8.115 (5.54), 9.01 5 (2.28 ), 9.032 (2.25), 9.089 (5.45), 9.373 (1.56), 9.389 (1.50).

Example 32

1-Ethanethioyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d ]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-amino)pyrido in dichloromethane (1.3 ml) [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (Example 7, 100 mg, 198 μmol) was added to a solution of Lawesson's reagent ( [CAS 38078-09-0], 80.0 mg, 198 μmol) was added and the mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The mixture was filtered, concentrated and the residue was purified by preparative TLC (silica, hexane, methanol) to give the title compound (26.5 mg, 95% purity, 24% yield).

LC-MS (Method 2): R _t = 1.22 min; MS (ESIpos): m/z = 522 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.56), 1.575 (5.41), 1.593 (5.45), 2.107 (0.70), 2.116 (0.52), 2.137 (0.44), 2.173 (0.47) ), 2.336 (0.42), 2.423 (12.40), 2.425 (12.89), 2.518 (5.66), 2.523 (3.88), 2.624 (7.27), 2.678 (0.56), 2.696 (16.00), 4.143 (0.45), 4 .151 (0.41 ), 4.177 (0.51), 4.299 (0.58), 4.325 (0.71), 4.362 (0.58), 5.706 (0.54), 5.712 (0.58), 5.724 (0.86), 5.729 (0.87), 5.741 (0.59), 5.74 7 (0.57 ), 5.758 (11.06), 7.350 (0.80), 7.369 (1.75), 7.389 (1.01), 7.545 (1.93), 7.563 (1.56), 7.789 (1.74), 7.809 (1.57), 9.041 (1.99), 9.0 59 (1.96 ), 9.105 (5.48), 9.400 (1.16), 9.415 (1.12).

Example 33

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylquinazolin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluor Roethan-1-ol

Ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylquinazolin-4-yl]amino}ethyl]-2-fluorophenyl in tetrahydrofuran (1.2.ml) } Sodium tetrahydridoborate (35.5 mg, 939 μmol) was added little by little to a solution of (difluoro)acetate (intermediate 173, 90.0 mg, 188 μmol), and the resulting mixture was stirred at room temperature for 1 hour. Aqueous hydrochloric acid (1 M) was added to the mixture until the solution reached ˜pH6 and the mixture was stirred for 15 minutes. The mixture was then extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride, filtered through a separatory funnel and concentrated. The residue was purified by preparative HPLC (basic method) to give the title compound (25.0 mg, 95% purity, 29% yield).

LC-MS (Method 2): R _t = 0.85 min; MS (ESIpos): m/z = 438.4 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.605 (4.77), 1.623 (4.90), 1.725 (13.70), 1.759 (13.80), 2.372 (16.00), 2.518 (1.60), 2.523 (1.18) ), 3.895 (0.50), 3.912 (0.55), 3.932 (0.94), 3.948 (0.98), 3.967 (0.47), 3.983 (0.45), 5.709 (0.81), 5.725 (1.91), 5.741 (0.76), 5.80 6 (0.73 ), 5.824 (1.13), 5.842 (0.72), 7.235 (0.87), 7.254 (1.91), 7.273 (1.11), 7.396 (0.68), 7.414 (1.05), 7.429 (0.53), 7.649 (1.63), 7.65 6 (1.91 ), 7.671 (2.47), 7.677 (2.04), 7.689 (0.52), 7.986 (0.91), 7.990 (0.91), 8.008 (0.86), 8.011 (1.67), 8.015 (0.96), 8.033 (0.76), 8.03 6 (0.79 ), 8.806 (1.24), 8.809 (1.22), 8.829 (1.33), 8.837 (1.44), 8.841 (1.44), 8.848 (1.25).

Example 34

1-Acetyl-4-[8-(hydroxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

In a microwave vial, 1-acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]-ethyl}amino)pyrido[3 ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (Example 7, 100 mg, 70% purity, 138 μmol) was dissolved in methanol (700 μl) and the mixture was irradiated with UV light (370 nm) for 5 days. The mixture was concentrated and the residue was purified by preparative TLC (silica, dichloromethane, methanol) to give the title compound (5 mg, 95% purity, 6% yield).

LC-MS (Method 2): R _t = 1.15 min; MS (ESIpos): m/z = 537 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.852 (0.76), 1.233 (2.80), 1.572 (2.33), 1.590 (2.33), 2.121 (7.80), 2.318 (1.51), 2.422 (7.26) ), 2.518 (16.00), 2.523 (11.33), 2.621 (3.04), 2.678 (1.33), 2.687 (0.93), 3.304 (0.77), 5.007 (0.64), 5.013 (0.85), 5.025 (2.33), 5. 047 (1.05 ), 5.059 (1.28), 5.064 (0.62), 5.721 (0.45), 7.364 (0.76), 7.383 (0.47), 7.540 (0.84), 7.559 (0.66), 7.782 (0.75), 7.801 (0.65), 8.91 1 (0.92 ), 8.928 (0.91), 9.335 (0.51), 9.352 (0.50).

Example 35

1-Acetyl-4-[8-cyclopropyl-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl in acetonitrile (1.8 ml) and water (750 μl) }-amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (Example 7, 125 mg, 247 μmol), cyclopropanecarboxyl A mixture of acid (39 μl, 490 μmol), ammonium persulfate ([CAS 7727-54-0], 282 mg, 1.24 mmol) and silver nitrate (168 mg, 989 μmol) was heated to 80° C. for 24 hours. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was separated, dried and concentrated. The residue was subjected to preparative HPLC (basic method) to give the title compound (12 mg, 95% purity, 8% yield) as a white solid.

LC-MS (Method 2): R _t = 1.35 min; MS (ESIpos): m/z = 546.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.996 (0.72), 1.009 (0.90), 1.024 (0.83), 1.109 (1.30), 1.125 (1.28), 1.565 (4.60), 1.582 (4.63) ), 2.053 (0.57), 2.062 (0.54), 2.084 (3.60), 2.113 (16.00), 2.284 (0.42), 2.322 (1.24), 2.327 (1.65), 2.332 (1.27), 2.449 (12.76), 2. 518 (5.27 ), 2.523 (3.44), 2.625 (5.99), 2.660 (0.43), 2.664 (0.92), 2.669 (1.31), 2.673 (0.94), 3.306 (0.86), 3.779 (0.63), 3.909 (0.60), 5.70 6 (0.52 ), 5.722 (0.76), 5.737 (0.51), 7.341 (0.70), 7.361 (1.54), 7.380 (0.88), 7.540 (1.64), 7.558 (1.33), 7.778 (1.45), 7.798 (1.31), 8.72 5 (2.00 ), 8.742 (1.98), 9.217 (1.03), 9.234 (0.97).

Example 36

1-Acetyl-4-[8-(difluoromethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyri do[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl in dichloromethane (1.6 ml) and water (650 μl) }-amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (Example 7, 200 mg, 396 μmol) and zinc bis( To a mixture of difluoromethanesulfinate (665 mg, 95% purity, 2.14 mmol) was added trifluoroacetic acid (61 μl, 790 μmol), followed by 2-methylpropane-2-peroxol ([CAS 75 -91-2], 570 μl, 70% purity, 4.0 mmol) was added dropwise, and the mixture was stirred at 40°C for 22 hours. Additional zinc bis(difluoromethanesulfinate) (665 mg, 95% purity, 2.14 mmol) and 2-methylpropane-2-peroxol (570 μl, 70% purity, 4.0 mmol) were added and stirred. This was continued for 2 days at room temperature. The mixture was diluted with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was filtered through a separatory funnel and concentrated. The residue was purified by preparative HPLC (basic method) to give the title compound (29.0 mg, 99% purity, 13% yield) as a white solid.

LC-MS (Method 2): R _t = 1.30 min; MS (ESIpos): m/z = 556.2 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.586 (4.96), 1.604 (4.97), 1.960 (0.40), 2.101 (0.44), 2.121 (16.00), 2.151 (0.43), 2.280 (0.48) ), 2.291 (0.44), 2.318 (0.64), 2.323 (1.06), 2.327 (1.37), 2.331 (1.08), 2.336 (0.64), 2.360 (0.43), 2.452 (14.03), 2.518 (4.99), 2.5 23 (3.43 ), 2.619 (6.67), 2.665 (0.80), 2.669 (1.12), 2.673 (0.81), 3.835 (0.43), 3.861 (0.51), 3.873 (0.58), 3.892 (0.79), 3.905 (0.83), 3.94 9 (0.71 ), 3.992 (0.46), 5.720 (0.64), 5.737 (0.96), 5.755 (0.63), 7.355 (0.75), 7.374 (1.64), 7.394 (0.95), 7.522 (1.02), 7.553 (1.78), 7.57 1 (1.43 ), 7.657 (2.24), 7.782 (1.64), 7.792 (1.02), 7.801 (1.47), 9.180 (1.76), 9.195 (1.75), 9.558 (1.13), 9.575 (1.09).

Example 37

1-Acetyl-4-[8-(methoxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one

Reaction 1-acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d Starting from ]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (Example 7, 125 mg, 247 μmol) and methoxyacetic acid (38 μl, 490 μmol), Example It was performed as described for 35 . Purification by preparative HPLC (basic method) gave the title compound (23.0).

LC-MS (Method 2): R _t = 1.22 min; MS (ESIpos): m/z = 550.2 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (2.87), 1.589 (2.88), 2.098 (0.41), 2.118 (9.38), 2.283 (0.51), 2.322 (0.44), 2.327 (0.53) ), 2.332 (0.45), 2.422 (7.73), 2.518 (1.44), 2.523 (0.94), 2.619 (3.95), 3.366 (16.00), 3.373 (1.71), 3.896 (0.68), 3.908 (0.68), 3.9 20 (0.70 ), 3.929 (0.75), 3.949 (0.71), 4.967 (5.28), 5.718 (0.50), 7.342 (0.45), 7.362 (0.97), 7.381 (0.56), 7.539 (1.07), 7.558 (0.87), 7.77 9 (0.95 ), 7.799 (0.88), 8.946 (1.09), 8.962 (1.06), 9.337 (0.62), 9.354 (0.58).

Example 38

(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-8-ethyl-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino }ethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol (mixture of diastereomers)

Ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino} in tetrahydrofuran (2.0 ml) ethyl]-2-fluorophenyl}(difluoro)acetate (intermediate 173, 270 mg, 75% purity, 421 μmol) in a solution of bromo(ethyl)magnesium (530 μl, 3.2 M, 1.7 μl) at -78°C. mmol) was added, the cooling bath was removed and the mixture was stirred for 3 hours. The reaction was then quenched by slow addition of ethanol at room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC (basic method) and subsequent purification by preparative TLC (silica, dichloromethane, ethanol) to give the title compound (9 mg, 90% purity, 4% yield).

LC-MS (Method 2): R _t = 1.22 min; MS (ESIpos): m/z = 495 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.88 - 0.97 (m, 3 H) 1.27 (d, J=1.52 Hz, 3 H) 1.33 - 1.45 (m, 1 H) 1.47 - 1.63 (m, 4 H) 1.65 - 1.74 (m, 6 H) 2.39 - 2.45 (m, 3 H) 3.16 - 3.28 (m, 2 H) 3.75 - 3.97 (m, 1 H) 5.49 - 5.63 (m, 1 H) 5.70 - 5.87 (m, 1 H) 7.15 - 7.31 (m, 1 H) 7.33 - 7.44 (m, 1 H) 7.56 - 7.76 (m, 1 H) 8.72 - 8.85 (m, 1 H) 9.08 - 9.22 (m, 1 H) ).

Example 39

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-4-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-amino)pyrido[3 in toluene (1.5 ml) under argon atmosphere. ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (intermediate 148, 75.0 mg, 162 μmol) and 4-bromo-1-methyl-1H-pyra Sodium tert-butoxide (23.3 mg, 243 μmol), DavePhos [CAS 213697-53-1] (24 mg, 65 μmol), and tris(benzylideneacetone)-di in a solution of sol (33 μl, 320 μmol). Palladium(0) (37.0 mg, 40.5 μmol) was added and the mixture was stirred at 120° C. overnight. The mixture was then cooled to room temperature, filtered and concentrated. The residue was purified by preparative TLC (silica, dichloromethane, methanol) to give the title compound (1.30 mg, 95% purity, 1% yield).

LC-MS (Method 2): R _t = 1.16 min; MS (ESIneg): m/z = 542 [MH] ^-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.76), 1.572 (4.16), 1.590 (4.11), 1.840 (0.40), 1.878 (0.76), 1.918 (0.47), 2.318 (0.41) ), 2.323 (0.93), 2.327 (1.32), 2.331 (0.94), 2.337 (0.58), 2.344 (0.62), 2.362 (0.74), 2.382 (0.80), 2.414 (13.02), 2.465 (0.56), 2.4 70 (0.83 ), 2.518 (4.05), 2.523 (2.85), 2.622 (5.18), 2.665 (0.81), 2.669 (1.12), 2.673 (0.76), 3.517 (1.35), 3.547 (1.00), 3.560 (1.46), 3.57 6 (0.90 ), 3.752 (16.00), 5.703 (0.65), 5.720 (0.98), 5.737 (0.63), 7.221 (3.67), 7.223 (3.63), 7.347 (0.62), 7.367 (1.34), 7.383 (4.03), 7.3 85 (4.21 ), 7.542 (1.42), 7.561 (1.14), 7.788 (1.25), 7.807 (1.13), 8.993 (1.43), 9.009 (1.41), 9.067 (3.86), 9.364 (1.08), 9.382 (1.03).

Example 40

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-3-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

Reaction 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine- 6-yl]-1,4lambda ⁵ -azaphosphinan-4-one (intermediate 148, 75.0 mg, 162 μmol) and 3-bromo-1-methyl-1H-pyrazole (52.1 mg, 324 μmol) Starting as described for Example 39, the title compound (60 mg, 95%) was obtained.

LC-MS (Method 2): R _t = 1.17 min; MS (ESIpos): m/z = 544 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.571 (4.35), 1.589 (4.28), 1.872 (0.76), 1.910 (0.43), 2.304 (0.56), 2.316 (0.82), 2.322 (0.71) ), 2.327 (0.80), 2.332 (0.76), 2.337 (0.77), 2.351 (0.52), 2.411 (14.18), 2.518 (0.95), 2.523 (0.69), 2.619 (5.51), 3.686 (16.00), 3. 727 (0.98 ), 3.739 (1.25), 3.769 (0.97), 3.779 (1.03), 5.698 (0.67), 5.715 (1.03), 5.733 (0.66), 5.779 (3.76), 5.784 (3.72), 7.343 (0.64), 7.36 2 (1.37 ), 7.382 (0.80), 7.490 (2.98), 7.495 (2.91), 7.538 (1.50), 7.556 (1.20), 7.789 (1.33), 7.809 (1.20), 8.995 (1.55), 9.011 (1.50), 9.06 0 (4.13 ), 9.374 (1.11), 9.391 (1.06).

Example 41

1-(methanesulfonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4 -d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-amino)pyrido[3 in dichloromethane (1.0 ml) at room temperature. ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (intermediate 148, 50.0 mg, 108 μmol) was added to a solution of N,N-diisopropylethylamine ( 38 μl, 220 μmol) was added followed by methanesulfonic anhydride (20.7 mg, 119 μmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with toluene and concentrated. The residue was purified by preparative HPLC (basic method) to give the title compound (37.3 mg, 95% purity, 61% yield).

LC-MS (Method 2): R _t = 1.14 min; MS (ESIpos): m/z = 542 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.575 (4.39), 1.592 (4.37), 2.085 (0.71), 2.425 (14.72), 2.455 (1.14), 2.518 (4.72), 2.523 (3.36) ), 2.623 (5.50), 3.015 (16.00), 3.301 (0.60), 3.599 (0.76), 3.632 (0.83), 3.723 (0.53), 3.738 (0.42), 3.759 (0.63), 3.771 (0.69), 3.7 87 (0.41 ), 5.708 (0.68), 5.725 (1.06), 5.742 (0.66), 7.350 (0.64), 7.369 (1.38), 7.388 (0.80), 7.545 (1.50), 7.563 (1.20), 7.785 (1.32), 7.80 4 (1.19 ), 9.022 (1.57), 9.038 (1.53), 9.101 (4.11), 9.103 (3.96), 9.368 (1.17), 9.385 (1.10).

Example 42

1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

Example 42 was obtained as a by-product of intermediate 156, which was separated by preparative HPLC: 4.00 mg (95% purity, 5% yield).

LC-MS (Method 2): R _t = 0.81 min; MS (ESIpos): m/z = 522.7 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.58 - 1.66 (m, 3 H) 1.87 - 2.39 (m, 2 H) 2.12 (s, 4 H) 2.27 - 2.38 (m, 1 H) 2.53 - 2.55 (m, 5 H) 3.44 - 3.58 (m, 1 H) 3.70 - 3.84 (m, 1 H) 3.93 (br s, 3 H) 4.15 - 4.34 (m, 1 H) 5.73 (s, 1 H) 5.76 - 5.86 (m, 1 H) 7.23 - 7.30 (m, 1 H) 7.40 - 7.48 (m, 1 H) 7.64 - 7.72 (m, 1 H) 9.18 (br d, J=7.10 Hz, 1 H) 9.26 (br d, J=4.31 Hz, 2 H).

Example 43

{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4-d ]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetic acid

Ethyl {3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyri in ethanol (450 μl) [3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetate (Intermediate 159, 150 mg, 266 μmol) was added to a solution of aqueous potassium hydroxide (670 μmol). μl, 2.0 M, 1.3 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The mixture was concentrated, diluted with water and purified by solid phase extraction chromatography (C18 SPE, water, methanol) to give the title compound (135 mg, 90% purity, 85% yield).

LC-MS (Method 2): R _t = 0.56 min; MS (ESIpos): m/z = 536.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.085 (1.87), 1.103 (1.99), 1.151 (1.16), 1.168 (1.21), 1.235 (0.44), 1.617 (4.70), 1.635 (4.71) ), 2.008 (0.48), 2.117 (16.00), 2.318 (0.66), 2.323 (0.77), 2.327 (1.04), 2.331 (0.75), 2.337 (0.43), 2.456 (13.46), 2.518 (2.45), 2. 523 (1.78 ), 2.665 (0.46), 2.669 (0.61), 2.673 (0.44), 3.165 (1.88), 3.376 (0.65), 3.442 (0.77), 3.502 (0.97), 3.530 (0.58), 3.754 (0.62), 3.78 3 (0.65 ), 3.953 (0.42), 5.793 (0.71), 5.810 (1.08), 5.828 (0.69), 6.940 (0.65), 7.280 (0.84), 7.299 (1.80), 7.319 (1.03), 7.502 (0.73), 7.51 9 (1.20 ), 7.535 (0.58), 7.678 (0.60), 7.697 (1.05), 7.715 (0.55), 9.289 (1.31), 9.294 (1.74), 9.300 (1.47), 9.305 (1.55), 9.328 (1.24), 9.33 3 (1.01 ), 9.357 (1.20), 9.362 (1.01), 9.601 (0.40).

Example 44

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-N-cyclopropyl-2,2-difluoroacetamide

{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl) in a solution of cyclopropanamine (42 μl, 600 μmol) )-2-Methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetyl chloride (Intermediate 160, equivalent of 33.3 mg, 60.0 μmol) ) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated and purified by preparative HPLC (basic method) to give the title compound (10.4 mg, 95% purity, 29% yield).

LC-MS (Method 2): R _t = 0.87 min; MS (ESIpos): m/z = 575.6 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.561 (0.44), 0.572 (1.02), 0.575 (1.09), 0.582 (1.63), 0.590 (1.99), 0.601 (0.74), 0.663 (0.74) ), 0.674 (1.37), 0.681 (1.49), 0.693 (1.86), 0.697 (1.04), 0.712 (0.49), 1.107 (16.00), 1.599 (3.42), 1.617 (3.42), 2.117 (10.44), 2. 318 (0.51 ), 2.322 (0.83), 2.327 (0.98), 2.332 (0.72), 2.336 (0.42), 2.414 (11.46), 2.518 (3.11), 2.523 (2.13), 2.664 (0.54), 2.669 (0.75), 2.6 73 (0.54 ), 2.762 (0.40), 2.770 (0.62), 2.781 (0.62), 2.789 (0.40), 4.190 (1.06), 5.741 (0.55), 5.758 (1.01), 5.776 (0.55), 7.283 (0.60), 7.30 2 (1.32 ), 7.322 (0.76), 7.469 (0.51), 7.487 (0.85), 7.503 (0.41), 7.689 (0.42), 7.707 (0.75), 9.051 (0.94), 9.062 (0.92), 9.147 (0.69), 9.16 4 (0.67 ), 9.256 (2.50), 9.262 (1.44), 9.268 (1.40), 9.288 (0.75).

Example 45

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N,N-dimethylacetamide

The reaction was carried out as described for Example 44 using intermediate 160 and N-methylmethanamine (300 μl, 2.0 M, 600 μmol) to give the title compound (19.6 mg, 95% purity, 55% yield) did.

LC-MS (Method 2): R _t = 0.88 min; MS (ESIpos): m/z = 563.6 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d, J=7.10 Hz, 3 H) 1.95 - 2.09 (m, 1 H) 2.12 (s, 4 H) 2.24 - 2.38 (m, 1 H) 2.40 (s, 3 H) 2.94 - 2.99 (m, 6 H) 3.42 - 3.55 (m, 1 H) 3.77 (q, J=11.83 Hz, 1 H) 3.86 - 4.00 (m, 1 H) 4.18 - 4.32 ( m, 1 H) 5.71 - 5.78 (m, 1 H) 7.31 (t, J=7.73 Hz, 1 H) 7.49 (t, J=6.72 Hz, 1 H) 7.71 (br t, J=7.22 Hz, 1 H ) 9.17 (br d, J=6.84 Hz, 1 H) 9.24 - 9.31 (m, 2 H).

Example 46

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4 -d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroacetamide

The reaction was carried out as described for Example 44 using intermediate 160 and ammonia (86 μl, 7.0 M, 600 μmol) to give the title compound (19.6 mg, 95% purity, 55% yield).

LC-MS (Method 2): R _t = 0.77 min; MS (ESIpos): m/z = 535.6 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.798 (0.88), 0.802 (0.50), 0.814 (0.96), 0.821 (0.99), 0.840 (0.50), 0.886 (0.50), 0.904 (1.01) ), 0.923 (0.46), 1.035 (3.23), 1.052 (6.84), 1.070 (3.26), 1.160 (0.44), 1.232 (1.86), 1.602 (4.96), 1.619 (4.95), 1.907 (0.48), 2.00 5 (0.51 ), 2.117 (14.61), 2.318 (1.36), 2.323 (2.42), 2.327 (3.20), 2.331 (2.34), 2.336 (1.20), 2.414 (16.00), 2.518 (12.04), 2.523 (8.26), 2 .660 (0.93 ), 2.665 (2.03), 2.669 (2.84), 2.673 (2.01), 2.678 (0.91), 3.159 (0.75), 3.171 (0.80), 3.364 (0.81), 3.404 (0.68), 3.417 (0.64), 3.42 2 (1.61 ), 3.435 (1.70), 3.439 (1.62), 3.452 (1.72), 3.457 (0.76), 3.469 (0.71), 3.484 (0.59), 3.511 (0.58), 3.754 (0.53), 3.785 (0.58), 4.34 7 (1.10 ), 4.360 (2.10), 4.372 (1.05), 5.758 (10.50), 5.775 (1.27), 5.793 (0.79), 7.282 (0.86), 7.301 (1.87), 7.320 (1.07), 7.483 (0.74), 7.5 00 (1.26 ), 7.516 (0.61), 7.686 (0.62), 7.704 (1.12), 7.723 (0.57), 8.137 (1.70), 8.408 (1.98), 9.145 (1.09), 9.162 (1.04), 9.251 (1.00), 9.25 6 (2.56 ), 9.262 (2.93), 9.267 (2.52), 9.292 (1.20).

Example 47

2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N-methylacetamide

The reaction was carried out as described for Example 44 using intermediate 160 and ammonia (86 μl, 7.0 M, 600 μmol) to give the title compound (19.6 mg, 95% purity, 55% yield).

LC-MS (Method 2): R _t = 0.78 min; MS (ESIpos): m/z = 549.5 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d, J=6.84 Hz, 3 H) 1.95 - 2.08 (m, 1 H) 2.12 (s, 4 H) 2.27 - 2.37 (m, 1 H) 2.41 (s, 3 H) 2.73 (d, J=4.56 Hz, 3 H) 3.43 - 3.55 (m, 1 H) 3.77 (q, J=12.00 Hz, 1 H) 3.86 - 3.99 (m, 1 H) 4.19 - 4.31 (m, 1 H) 5.71 - 5.78 (m, 1 H) 7.30 (t, J=7.86 Hz, 1 H) 7.50 (t, J=6.84 Hz, 1 H) 7.71 (br t, J=7.35 Hz , 1 H) 8.99 (br d, J=4.56 Hz, 1 H) 9.16 (br d, J=6.84 Hz, 1 H) 9.24 - 9.30 (m, 2 H).

Example 48

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoroacetamide

As described in Intermediate 162, ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl ]-2-Fluorophenyl}(difluoro)acetate (Intermediate 161, 142 mg, 296 μmol) and ammonia (300 μl, 7.0 M, 2.1 mmol) were reacted to obtain the title compound (16.0 mg, 91% purity, 11 % yield) was obtained.

LC-MS (Method 2): R _t = 0.78 min; MS (ESIpos): m/z = 452.6 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.593 (5.12), 1.610 (5.07), 1.688 (7.43), 1.692 (7.59), 1.722 (7.62), 1.726 (7.34), 2.427 (16.00) ), 2.518 (0.90), 2.523 (0.62), 5.750 (0.84), 5.767 (1.30), 5.785 (0.83), 7.279 (1.02), 7.298 (2.17), 7.317 (1.23), 7.477 (0.76), 7.49 4 (1.28 ), 7.511 (0.63), 7.693 (0.68), 7.710 (1.22), 7.728 (0.62), 8.137 (1.66), 8.407 (1.91), 8.949 (1.98), 8.965 (2.00), 9.087 (4.77), 9.28 4 (1.47 ), 9.302 (1.39).

Example 49

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-N-ethyl-2,2-difluoroacetamide

As described in Intermediate 162, ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl ]-2-Fluorophenyl}(difluoro)acetate (Intermediate 161, 142 mg, 296 μmol) and ethanamine (520 μl, 2.0 M, 1.0 mmol) were reacted to obtain the title compound (19 mg, 95% purity, 19% yield) was obtained.

LC-MS (Method 2): R _t = 0.90 min; MS (ESIpos): m/z = 480.2 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (1.05), 1.045 (1.37), 1.064 (3.26), 1.081 (1.48), 1.105 (16.00), 1.142 (0.68), 1.639 (1.40) ), 1.657 (1.40), 1.714 (2.83), 1.747 (2.80), 3.185 (0.43), 3.203 (0.61), 3.221 (0.42), 7.341 (0.61), 9.221 (0.89).

Example 50

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N,N-dimethylacetamide

As described in Intermediate 162, ethyl {3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl ]-2-Fluorophenyl}(difluoro)acetate (Intermediate 161, 142 mg, 296 μmol) and dimethylamine (540 μl, 2.0 M, 1.1 mmol) were reacted to obtain the title compound (8.00 mg, 96% purity, 7% yield) was obtained.

LC-MS (Method 2): R _t = 0.93 min; MS (ESIpos): m/z = 480.5 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.826 (0.64), 0.852 (0.75), 0.967 (1.01), 1.107 (1.04), 1.144 (0.68), 1.232 (2.61), 1.372 (0.57) ), 1.496 (0.46), 1.605 (3.58), 1.623 (3.54), 1.692 (5.83), 1.694 (5.88), 1.726 (5.94), 1.729 (5.83), 2.331 (3.23), 2.337 (1.41), 2.43 9 (6.28 ), 2.518 (16.00), 2.523 (11.18), 2.673 (3.18), 2.678 (1.38), 2.960 (8.48), 2.971 (6.31), 5.743 (0.45), 5.761 (0.70), 5.778 (0.47), 7. 301 (0.66 ), 7.320 (1.41), 7.340 (0.85), 7.478 (0.58), 7.495 (0.93), 7.512 (0.48), 7.710 (0.49), 7.730 (0.83), 8.979 (0.91), 8.995 (0.93), 9.10 8 (2.71 ).

Example 51

2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N-methylacetamide

Following General Procedure 6, 6-(dimethylphosphoryl)-2-methylpyrido-[3,4-d]pyrimidin-4-ol (Intermediate 71, 49.0 mg, 207 μmol) and 2-{3-[ (1R)-1-Aminoethyl]-2-fluorophenyl}-2,2-difluoro-N-methylacetamide Starting from hydrogen chloride (1/1) (intermediate 163, 70.1 mg, 248 μmol), The title compound was obtained (5.00 mg, 5% yield).

LC-MS (Method 2): R _t = 0.88 min; MS (ESIpos): m/z = 466.6 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.232 (0.56), 1.590 (1.36), 1.608 (1.34), 1.686 (1.92), 1.690 (1.96), 1.720 (1.91) ), 1.724 (1.89), 2.331 (1.12), 2.336 (0.51), 2.420 (4.42), 2.518 (6.16), 2.523 (4.16), 2.673 (1.12), 2.678 (0.51), 2.723 (1.64), 2.73 5 (1.58 ), 4.191 (1.18), 7.301 (0.54), 8.946 (0.52), 8.962 (0.56), 9.092 (1.16).

Example 52

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-methyl-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 in dimethyl carbonate (0.5 ml) ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one (intermediate 226, 51.7 mg, 115 μmol), N,N,N-tributylbutan-1- A solution of amidium bromide (1.85 mg, 5.75 μmol) and (S)-(-)-proline (660 μg, 5.8 μmol) was stirred at 90°C for 2 days. The residue was concentrated and purified by flash chromatography (silica, dichloromethane, methanol) to give the title compound (21.0 mg, 98% purity, 39% yield).

LC-MS (Method 2): R _t = 1.02 min; MS (ESIneg): m/z = 462 [MH] ^-

1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (d, J=7.10 Hz, 3 H) 1.84 - 1.99 (m, 2 H) 2.29 (s, 3 H) 2.43 (s, 5 H) 2.69 - 2.94 (m, 4 H) 5.63 - 5.86 (m, 1 H) 7.08 - 7.39 (m, 2 H) 7.47 - 7.56 (m, 1 H) 7.66 - 7.76 (m, 1 H) 8.92 - 9.01 (m, 1 H) ) 9.11 (s, 1 H) 9.23 - 9.30 (m, 1 H).

Example 53

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(propan-2-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one

4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-pyrido[3,4- d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one in a solution of hydrogen chloride (1/1) (intermediate 164, 430 mg, 860 μmol) in acetone (12 ml) Sodium cyanoborohydride (81.1 mg, 1.29 mmol) and acetic acid (120 μl) were added and the mixture was stirred at room temperature overnight. Aqueous sodium hydroxide (1 M) was then added and the mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated and the residue was diluted with DMSO. The formed solid was filtered and dried to give the title compound (275 mg, 90% purity, 57% yield).

LC-MS (Method 2): R _t = 1.24 min; MS (ESIpos): m/z = 507 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.04 - 1.15 (m, 6 H) 1.53 - 1.63 (m, 3 H) 1.92 - 2.14 (m, 1 H) 2.42 (s, 3 H) 2.62 (s , 4 H) 3.01 - 3.15 (m, 1 H) 3.51 - 3.86 (m, 2 H) 4.59 - 4.77 (m, 1 H) 5.65 - 5.79 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.49 - 7.60 (m, 1 H) 7.74 - 7.84 (m, 1 H) 8.99 - 9.03 (m, 1 H) 9.04 - 9.06 (m, 1 H) 9.37 - 9.46 (m, 1 H).

Example 54

1-benzyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one

1-Benzyl-4-[4-({(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoro- in THF (1.5 ml) 2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one To a solution of (150 mg, 211 μmol) was added tetrabutylammonium fluoride (840 μl, 1.0 M in THF, 840 μmol) and the mixture was stirred at 40° C. overnight. The mixture was concentrated and the residue was purified by flash chromatography (silica, hexane, ethyl acetate, dichloromethane, ethanol) to give the title compound (130 mg, 90% purity, 93% yield).

LC-MS (Method 2): R _t = 1.23 min; MS (ESIpos): m/z = 599 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.914 (0.40), 0.932 (0.67), 1.153 (0.81), 1.171 (1.59), 1.189 (1.47), 1.199 (6.51), 1.224 (6.70) ), 1.233 (1.48), 1.251 (0.40), 1.587 (4.89), 1.605 (4.81), 1.876 (0.44), 1.907 (1.12), 1.953 (0.48), 1.986 (2.75), 2.322 (0.49), 2.32 6 (0.68 ), 2.332 (0.58), 2.336 (0.43), 2.373 (0.82), 2.415 (16.00), 2.518 (1.88), 2.522 (1.24), 2.664 (0.42), 2.668 (0.58), 2.805 (0.92), 2.8 36 (1.03 ), 2.863 (0.45), 2.904 (0.65), 2.917 (0.52), 2.958 (0.67), 2.973 (0.50), 2.989 (0.44), 3.158 (0.84), 3.171 (0.78), 3.653 (6.02), 4.01 6 (0.57 ), 4.034 (0.57), 4.212 (0.43), 4.216 (0.44), 4.489 (0.44), 4.494 (0.43), 5.334 (8.36), 5.758 (5.35), 5.767 (0.82), 5.785 (1.24), 5.80 3 (0.79 ), 7.199 (0.78), 7.219 (1.81), 7.238 (1.25), 7.249 (0.56), 7.255 (0.67), 7.263 (1.07), 7.271 (0.84), 7.278 (0.93), 7.284 (0.72), 7.29 7 (0.84 ), 7.301 (0.88), 7.309 (0.79), 7.319 (1.30), 7.322 (1.39), 7.329 (0.72), 7.343 (4.65), 7.350 (4.87), 7.358 (11.05), 7.371 (0.62), 7.4 80 (0.43 ), 7.498 (0.40), 7.525 (0.49), 7.553 (0.63), 7.569 (0.43), 7.600 (0.69), 7.617 (1.16), 7.632 (0.62), 8.986 (1.61), 9.002 (1.60), 9.12 0 (4.22 ), 9.254 (1.32), 9.272 (1.26).

The examples shown in Table 6 were prepared from each pyrimidin-4-ol derivative and each amine according to General Procedure 6.

Example Table 6

The examples shown in Table 7 were prepared from each silyl protected alcohol derivative as described for Example 4.

Example Table 7

The examples shown in Table 8 were prepared from each halo aryl derivative and each phosphine oxide according to General Procedure 1.

Example Table 8

The examples shown in Table 9 were prepared according to General Procedure 3, and then the crude intermediates were converted directly from the respective N-Boc protected derivatives by General Procedure 7.

Example Table 9

The examples shown in Table 10 were prepared from each amine derivative according to general procedure 8.

Example Table 10

The examples shown in Table 11 were prepared from each amine derivative and each isocyanate according to general procedure 9.

Example Table 11

The examples shown in Table 12 were prepared from each amine derivative and each isocyanate according to general procedure 10.

Example Table 12

The examples shown in Table 13 were prepared from each amine derivative according to general procedure 7.

Example Table 13

The examples shown in Table 14 were prepared from each amine derivative according to general procedure 11.

Example Table 14

Experimental Section - Biological Assays

Examples were tested at least once in selected biological assays. If tested more than once, data are reported as mean or median, where:

· The average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested,

· The median represents the middle number of a group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two intermediate values.

The examples were synthesized more than once. When synthesized more than once, data from biological assays represent mean or median values calculated using data sets obtained from testing of more than one synthetic batch.

Biochemical assay: hK-RasG12C interaction assay with hSOS1

In this assay, the equilibrium interaction of human SOS1 (SOS1) and human K-Ras ^G12C (K-RasG12C) was quantified. Detection of the interaction is accomplished by homogeneous time-resolved fluorescence resonance energy transfer from anti-GST-europium bound to GST-K-RasG12C (FRET donor) to anti-6His-XL665 bound to His-tagged hSOS1 (FRET-acceptor). This was achieved by measuring (HTRF).

Assay buffer was 5 mM HEPES pH 7.4 (Applichem), 150 mM NaCl (Sigma), 10 mM EDTA (Promega), 1 mM DTT (Thermofisher), 0.05%. BSA fraction V, pH 7.0 (ICN Biomedicals), contained 0.0025% (v/v) IGEPAL (Sigma) and 100 mM KF (FLUKA).

Expression and purification of N-terminally GST-tagged human K-RasG12C (named GST-hK-RasG12C) and N-terminally His-tagged human SOS1 (named His10-hSOS1) were described in WO 2019/201848. , page 220, lines 12 - 34 and page 222, lines 13 - 25 (expression) and page 222, lines 26 to page 223, line 17 (purification). The concentration of the protein batch used was optimized to be within the linear range of the HTRF signal. Ras working solutions were prepared in assay buffer typically containing 10 nM GST-hK-RasG12C and 2 nM anti-GST-Eu(K) (Cisbio, France). SOS1 working solutions were prepared in assay buffer typically containing 20 nM His-hSOS1 and 10 nM anti-6His-XL665 (Cisbio, France). Inhibitor control solutions were prepared in assay buffer containing 10 nM anti-6His-XL665 without SOS1.

50 nl of a 100-fold concentrated solution of the test compound in DMSO was transferred to a black microtiter test plate (384 or 1536, Greiner Bio-One, Germany). For this purpose, a Hummingbird liquid handler (Digilab, Massachusetts, USA) or an Echo acoustic system (Labcyte, California, USA) was used.

All steps of the assay were performed at 20°C. A 2.5 μl volume of Ras working solution was added to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After a 2 minute preincubation, 2.5 μl of SOS1 working solution was added to all wells except those on the side of the test plate, which were subsequently filled with 2.5 μl of inhibitor control solution. After 60 min incubation, fluorescence was measured with Perasta (BMG, Germany) using an HTRF module (excitation 337 nm, emission 1: 620 nm, emission 2: 665 nm).

Ratiometric data (emission 2 divided by emission 1) were normalized using controls (DMSO = 0% inhibition, inhibition control wells with inhibitor control solution = 100% inhibition). Compounds were tested in duplicate at no more than 11 concentrations (for 20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM). IC50 values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).

Claims (23)

A compound of formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof:

here
X ₁ represents CH or N;
X ₂ represents CR ^a or N;
X ₃ represents CR ^a or N;
X ₄ represents CH or N;
Y represents O or S;
R ¹ , R ² are independently selected from C _1-4 alkyl, OR ^b or NR ^c R ^d ; or
R ¹ , R ² together with the phosphorus atom to which they are attached form a 4-7 membered heterocycloalkyl, wherein one or more carbon atoms are -O-, -NR ^e -, -S-, -S(O) -, S(O) ₂ - or -S(O)NR ^f -; wherein each remaining carbon atom may be optionally substituted by 1 or 2 CH ₃ or 1 -CH ₂ -CH ₃ ;
R ³ is selected from -H, -OH, -OMe, -CN, -NR ^p R ^q , or C _1-2 -alkyl optionally substituted with OH, OMe, CN or halogen;
R ⁴ is selected from -F, -Cl, -Br, -OH, -NH ₂ , -N(CH ₃ )H, -CH ₃ or -CF ₂ H;
R ⁵ represents -ABE, where
A represents -CR ^j R ^k - or is absent,
B represents -CR ^l R ^m - or is absent,
E is -H, -F, -OH, -OCH ₃ , -NH ₂ , -NH-CH ₃ , -N(CH ₃ ) ₂ , -N(CH ₃ )-OCH ₃ , -CN, -SO ₂ - CH ₃ , -NH-SO ₂ -CH ₃ , -N(CH ₃ )-SO ₂ -CH ₃ , -NH-C(O)-CH ₃ , -N(CH ₃ )-C(O)-CH ₃ , -S(=NH)(=O)-CH ₃ , -S(=N-CH ₃ )(=O)-CH ₃ , -C(O)-NH ₂ , -C(O)-NH(CH ₃ ), -C(O)-N(CH ₃ ) ₂ ; or
R ⁵ represents -SO ₂ -NR ⁿ R ^o ;
R ⁶ is selected from -H, halogen or -CH ₃ ;
R ^a is -H, halogen, -OH, -OCH ₃ , -CN, cyclopropyl, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , or halogen, -OH or -OCH ₃ , is selected from -CH ₃ , -CF ₃ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ or C _1-2 alkyl optionally substituted one or more times by -CN;
R ^b is -H (provided that only one R ^b can be H if both R ¹ and R ² are OR ^b ), -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl;
R ^c is selected from -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl;
R ^d is selected from -H, -CH ₃ , -CH ₂ -CH ₃ , -CH(CH ₃ ) ₂ or cyclopropyl;
R ^e is H, C1-C3-alkyl optionally substituted by one or more F, cyclopropyl, -C(O)-R ^g , -SO ₂ -CH ₃ , or -CH ₃ , halogen, -CF ₃ or -CF ₂ H; 5-membered heteroaryl optionally substituted;
R ^f is selected from H, -CH ₃ , or -CH ₂ -CH ₃ ;
R ^g is selected from -OH, -OCH ₃ , -CH ₃ , C _1-4 alkyl optionally substituted by halogen, or
-CH ₃ , CH ₂ CH ₃ , CF ₂ H, CF ₃ or a 5-membered heteroaryl optionally substituted by halogen, or
is selected from NR ^h R ⁱ ;
R ^h is selected from H or -CH ₃ ;
R ⁱ is selected from C _1-3 alkyl optionally substituted by halogen or from cyclopropyl;
R ^j and R ^k are independently selected from H, F or -CH ₃ or together with the carbon atom to which they are attached they form cyclopropyl;
R ^l and R ^m are independently selected from H, deuterium, or -CH ₃ , -CH ₂ -CH ₃ , cyclopropyl, or
or together with the carbon atom to which they are attached form cyclopropyl; or
R ⁿ and R ^o are independently selected from H, or C _1-4 alkyl optionally substituted by -OH, -OCH ₃ ; or
R ⁿ and R ^o together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl optionally containing additional heteroatoms selected from N or O, wherein the carbon atom of said heterocycloalkyl is H or C It may be optionally substituted by _1-4 alkyl, and the C _1-4 alkyl is again halogen, =O, -OH, -OCH ₃ , -NH ₂ , -NH-CH ₃ or -N(CH ₃ ) ₂ and the nitrogen atom of the heterocycloalkyl is optionally substituted with -C(O)-cyclopropyl or -C(O)-C _1-4 -alkyl, both of which are optionally substituted one or more times with F. can be;
R ^p and R ^q are independently selected from H, -CH ₃ or -CH ₂ -CH ₃ . 2. The compound according to claim 1, of formula (Ia): or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof:

here
X ₁ represents CH;
X ₂ represents CR ^a or N;
X ₃ represents CR ^a or N;
X ₄ represents CH or N;
Y represents O;
R ¹ , R ² are independently selected from -CH ₃ , -CH ₂ -CH ₃ or -CH(CH ₃ ) ₂ ; or
R ¹ , R ² together with the phosphorus atom to which they are attached form:

;
R ³ is selected from -CH ₃ , -CHF ₂ , -CF ₃ or -Cl;
R ⁴ is selected from -H, -NH ₂ or -CH ₃ ;
R ⁵ is selected from:
-Br,
-CF ₂ -H, -CF ₂ -F, -CF ₂ -CH ₃ , -CF ₂ -CH ₂ -OH, -CF ₂ -CD ₂ -OH, -CF ₂ -CH ₂ -OCH ₃ , -CF ₂ -CH(CH ₃ )-OH, -CF ₂ -CH(CH ₂ -CH ₃ )-OH, -CF ₂ -C(CH ₃ ) ₂ -OH, CF ₂ -C(CH ₃ ) ₂ -OCH ₃ , -CF ₂ -CH(CH(CH ₃ ) ₂ )-OH, -CF ₂ -CH(C(CH ₃ ) ₃ )-OH, -CF ₂ -C(CH ₃ )(CH ₂ -CH ₂ -CH ₂ -CH ₃ )-OH,
-CF ₂ -C(=O)-CH(CH ₃ ) ₂ , -CF ₂ -C(=O)-C(CH ₃ ) ₃ ,
-CF ₂ -C(=O)-OH, -CF ₂ -C(=O)-NH ₂ , -CF ₂ -C(=O)-N(CH ₃ ) ₂ , -CF ₂ -C(=O )-NH-CH ₃ , -CF ₂ -C(=O)-NH-CH ₂ -CH ₃ , -CF ₂ -C(=O)-NH-cyclopropyl,
-CF ₂ -CH ₂ -NH-SO ₂ -CH ₃ , -CF ₂ -CH ₂ -N(CH ₃ )-SO ₂ -CH ₃ , -CF ₂ -CH ₂ -NH-C(=O)-CH ₃ or -CF ₂ -CH ₂ -N(CH ₃ );
R ⁶ is selected from -H, -CH ₃ , -Fl or -Cl;
R ^a is -H, -CH ₃ , -CH ₂ -CH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ -OH, -CH ₂ -O-CH ₃ , -OH, -OCH ₃ or from cyclopropyl being chosen;
R ^r is selected from: -H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -phenyl, -C(=O)-H, -C(=O)-CH ₃ , -C (=O)-CH ₂ F, -C(=O)-CH(CH ₃ ) ₂ , -C(=O)-CH(CH ₃ )-OH, -C(=O)-CH(CH ₃ ) -O-CH ₃ ,

-C(=O)-CH ₂ -CN, -C(=O)-CH ₂ -O-CH ₃ ,
-C(=O)-OC(CH ₃ ) ₃ , -C(=O)-O-CH ₂ -CH ₃ ,
-C(=O)-NH ₂ , -C(=O)-N(CH ₃ ) ₂ , -C(=O)-CH ₂ -CHF ₂ , -C(=O)-NH-cyclopropyl,
-C(=S)-CH ₃ , -SO ₂ -CH ₃ ,

;
R ^s is selected from -CH ₃ or -CD ₃ ;
R ^t is selected from -H or D. _The compound according to claim ₁ or 2 _, wherein only one of X ₁ , mixture. The compound according to claim 1 or 2, wherein Y represents O, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. The compound according to claim 1 or 2, wherein R ¹ and R ² are selected from C _1-4 alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. . The method according to claim 1 or 2, wherein R ¹ and R ² together with the phosphorus atom to which they are attached

A compound that forms a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. The compound according to claim 1 or 2, wherein R ³ is selected from C _1-2 -alkyl optionally substituted with 1 to 3 F or stereoisomers, tautomers, N-oxides, hydrates, solvents thereof. cargo or salt, or mixtures thereof. The compound according to claim 1 or 2, wherein R ⁶ is selected from -F, -Cl, -H or -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof. , or mixtures thereof. The compound according to claim 1 or 2, wherein R ^a is selected from -H, -Cl, -CH ₃ , -CF ₃ or -CF ₂ H, or a stereoisomer, tautomer, N-oxide thereof, Hydrate, solvate or salt, or mixtures thereof. The compound or stereoisomer, tautomer thereof according to claim 1, wherein R ^j and R ^k together with the carbon atom to which they are attached form cyclopropyl, or both are selected from -F, or both -CH ₃ Isomers, N-oxides, hydrates, solvates or salts, or mixtures thereof. The compound according to claim 1 or 2, wherein R ¹ and R ² are both -CH ₃ or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. The compound according to claim 1 or 2, wherein R ⁵ is -CF ₃ and R ⁶ is -F, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. The compound according to claim 1 or 2, wherein X ² is N and X ³ is CH, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. 2. Morpholine or N-acetylpiperazine according to claim 1, wherein R ⁿ and R ^o together with the nitrogen to which they are attached are both optionally substituted with one or two -CH ₃ , -CF ₃ or -CF ₂ H. A compound that forms a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. The method of claim 1 or 2, wherein any substituent from any one of claims 3 to 14 can be combined with any other substituent or substituents from any of claims 3 to 14. A compound or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or mixture thereof. 2. The compound according to claim 1, selected from the group consisting of:
6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine- 4-amine
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine -4-amine
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
1-benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-benzyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1,4 lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol
1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol
6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidine- 4-amine
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-2-methylpropan-2-ol
1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[2,3-d]pyrimidin-4-yl}amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
6-(dimethylphosphoryl)-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrido Mydin-4-amine
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d] Pyrimidin-4-amine
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7 -Dimethylpyrido[2,3-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
1-{3-[(1R)-1-({6-[di(propan-2-yl)phosphoryl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-yl} amino) ethyl]-2-fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol
6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[ 2,3-d]pyrimidin-4-amine
(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]- 2-fluorophenyl}-1,1-difluoro-2-methylhexan-2-ol (mixture of diastereomers)
6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 1)
6-(dimethylphosphoryl)-2-methyl-N-{1-[2-(trifluoromethyl)pyridin-4-yl]ethyl}pyrido[3,4-d]pyrimidin-4-amine ( Enantiomer 2)
4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-6-(dimethylphosphoryl )-2-methylpyrido[3,4-d]pyrimidin-8-ol
1-Acetyl-4-[8-hydroxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carbaldehyde
1-Ethanethioyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d ]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylquinazolin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluor Roethan-1-ol
1-Acetyl-4-[8-(hydroxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[8-cyclopropyl-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[8-(difluoromethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyri do[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[8-(methoxymethyl)-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido [3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
(2RS)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-8-ethyl-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino }ethyl]-2-fluorophenyl}-1,1-difluorobutan-2-ol (mixture of diastereomers)
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-4-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(1-methyl-1H-pyrazol-3-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-(methanesulfonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4 -d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4-d ]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}(difluoro)acetic acid
2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-N-cyclopropyl-2,2-difluoroacetamide
2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N,N-dimethylacetamide
2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ amino-azaphosphinan-4-yl)-2-methylpyrido[3,4 -d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroacetamide
2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3,4- d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoro-N-methylacetamide
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoroacetamide
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-N-ethyl-2,2-difluoroacetamide
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N,N-dimethylacetamide
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro Phenyl}-2,2-difluoro-N-methylacetamide
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-methyl-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- yl]-1-(propan-2-yl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-benzyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
6-(dimethylphosphoryl)-N-{(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl}-2-methylpyrido[3,4-d]pyrimidine -4-amine
N-[(1R)-1-(3-bromo-2-fluorophenyl)ethyl]-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-amine
1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[2,5-dimethyl-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-2,5-dihydro-1H-1lambda ⁵ amino-phosphol-1-one
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoro( ^2H ₂ )ethan-1-ol
1-(4-{[(1R)-1-{3-[1,1-difluoro-2-hydroxy( ^2H ₂ )ethyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ -phospholan-1-one
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-2,2-difluoroethane-1-ol
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
2-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluo lophenyl}-2,2-difluoroethane-1-ol
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluorobutan-2-ol (diastereomer 1)
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol (diastereomer 1)
1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (mixture of diastereomers)
1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (diastereomer 1)
1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-1,1-difluoro-2-methylpropan-2-ol (diastereomer 2)
1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (mixture of diastereomers)
1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (diastereomer 1)
1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}-2-methylpropan-2-ol (diastereomer 2)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino )ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (mixture of diastereomers)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 1)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino )ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (mixture of diastereomers)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 3)
(2R*)-1-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino ) ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 4)
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (mixture of diastereomers)
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 1)
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 2)
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 3)
(2R*)-1,1-difluoro-1-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl] Pyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]phenyl}propan-2-ol (diastereomer 4)
1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-2,5-dihydro-1H-1lambda ⁵ amino-phosphol-1-one
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoropropan-2-ol
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3-methylbutan-2-ol (diastereomer 2)
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluorobutan-2-ol (diastereomer 2)
(2R*)-1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl ]-2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)
tert-Butyl 4-[2,8-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] Pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxylate
6-(diethylphosphoryl)-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[3,4-d]pyri Mydin-4-amine
1-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
N-{(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido [3,4-d]pyrimidin-4-amine
1-[4-({(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- 1]-1lambda ⁵ amino-phospholan-1-one
6-(diethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3,4-d]pyrimidine -4-amine
N-{(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine- 4-amine
6-[di(propan-2-yl)phosphoryl]-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[3, 4-d]pyrimidin-4-amine
1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1lambda ⁵ amino-phospholan-1-one
1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine- 6-yl]-1lambda ⁵ amino-phospholan-1-one
6-(dimethylphosphoryl)-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3- d]pyrimidin-4-amine
6-[di(propan-2-yl)phosphoryl]-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[ 2,3-d]pyrimidin-4-amine
1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]-2-fluo Lophenyl}-1,1-difluoro-2-methylpropan-2-ol
1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1lambda ⁵ amino-phos pollan-1-on
1-benzyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1, 4lambda ⁵ amino-azaphosphinan-4-one
6-(dimethylphosphoryl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}quinazolin-4-amine
1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1lambda ⁵ amino-phospholan-1-one
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[di(propan-2-yl)phosphoryl]-2-methylpyrido[3 ,4-d]pyrimidin-4-amine
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-3-methylbutan-2-one
1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluoro phenyl}-1,1-difluoro-3,3-dimethylbutan-2-one
1-(4-{[(1R)-1-{3-[(2R*)-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ amino-phospholan-1-one (diastereomer 1)
1-(4-{[(1R)-1-{3-[(2R*)-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- Methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda ⁵ amino-phospholan-1-one (diastereomer 2)
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoropropan-2-ol (diastereomer 2)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (mixture of diastereomers)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (diastereomer 1)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3 ,4-d]pyrimidin-4-amine (diastereomer 2)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (mixture of diastereomers)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (diastereomer 1)
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d ]Pyrimidin-4-amine (diastereomer 2)
N-{(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidine- 4-amine
N-{(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2 -Methylpyrido[3,4-d]pyrimidin-4-amine
1-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1lambda ⁵ amino-phospholan-1-one
1-{3-[(1R)-1-{[6-(diethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluo Lophenyl}-1,1-difluoro-2-methylpropan-2-ol
2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2,8-dimethylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-2,2-difluoroethane-1-ol
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methyl-7-(trifluoromethyl)pyrido [2,3-d]pyrimidin-4-amine
1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidine -6-yl]-1lambda ⁵ amino-phospholan-1-one
1-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylquinazolin-6-yl]-1lambda ⁵ amino- Phospholan-1-one
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-(dimethylphosphoryl)-2-methylquinazolin-4-amine
N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-6-[di(propan-2-yl)phosphoryl]-2,7-dimethylpyrido [2,3-d]pyrimidin-4-amine
2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (mixture of diastereomers)
2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (diastereomer 1)
2-{3-[(1R)-1-({6-[ethyl(methyl)phosphoryl]-2-methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2 -Fluorophenyl}-2,2-difluoroethane-1-ol (diastereomer 2)
2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (mixture of diastereomers)
2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (diastereomer 1)
2,2-difluoro-2-{2-fluoro-3-[(1R)-1-({2-methyl-6-[methyl(propan-2-yl)phosphoryl]pyrido[3, 4-d]pyrimidin-4-yl}amino)ethyl]phenyl}ethan-1-ol (diastereomer 2)
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 1)
(2R*)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl] -2-fluorophenyl}-1,1-difluoro-3,3-dimethylbutan-2-ol (diastereomer 2)
1-Acetyl-4-(2 _{-methyl-4-{[(1S)-1-[2-methyl-3-(trifluoromethyl)phenyl](2H4} ⁾ ethyl]amino}pyrido[3, 4-d]pyrimidin-6-yl)-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoroethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[3-(1,1-difluoro-2-methoxyethyl)phenyl]ethyl}amino)-2-methylpyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2, 3-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-Acetyl-4-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d ]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
(R)-1-(4-(2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d] pyrimidin-6-yl)-4-oxido-1,4-azaphosphinan-1-yl)ethan-1-one
1-Acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2S)-2-methoxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2R)-2-hydroxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-fluorocyclopropane-1-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carbonyl}cyclopropane-1-carbonitrile
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(2-methylpropanoyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(methoxyacetyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2R)-2-methoxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-hydroxycyclopropane-1-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -1]-1-[(2S)-2-hydroxypropanoyl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(oxetane-3-carbonyl)-1,4lambda ⁵ -azaphosphinan-4-one
1-[1-(difluoromethyl)cyclopropane-1-carbonyl]-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl }amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-(3,3-difluorocyclobutane-1-carbonyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl} Amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
3-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine -6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-yl}-3-oxopropanenitrile
1-(cyclopropanecarbonyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-1-(oxetane-3-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-[(2S)-2-hydroxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one
1-[(2R)-2-hydroxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one
1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine -6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carbonyl}cyclopropane-1-carbonitrile
1-(1-fluorocyclopropane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one
1-[1-(difluoromethyl)cyclopropane-1-carbonyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl) Phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-(3,3-difluorocyclobutane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl ]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1-(2-methylpropanoyl)-1,4lambda ⁵ -azaphosphinan-4-one
1-(cyclopropanecarbonyl)-4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl ]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-(1-hydroxycyclopropane-1-carbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one
1-(cyclopropanecarbonyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-[(2S)-2-methoxypropanoyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl} Amino) pyrido [3,4-d] pyrimidin-6-yl] -1,4 lambda ⁵ amino-azaphosphinan-4-one
1-(methoxyacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4 -d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-[1-(hydroxymethyl)cyclopropane-1-carbonyl]-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl ]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)methanesulfonamide
N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)acetamide
N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylmethanesulfonamide
N-(2-{3-[(1R)-1-({6-[1-(cyclopropanecarbonyl)-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl]-2- Methylpyrido[3,4-d]pyrimidin-4-yl}amino)ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylacetamide
4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6 -yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxamide
N-cyclopropyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ -azaphosphinan-1-carboxamide
N-(2,2-difluoroethyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyri nor[3,4-d]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxamide
4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- Il]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxamide
Ethyl 4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine- 6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate
N,N-dimethyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d ]pyrimidin-6-yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinan-1-carboxamide
Ethyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6 -yl]-4-oxo-1,4lambda ⁵ amino-azaphosphinane-1-carboxylate
1-Acetyl-4-[4-({(1R)-1-[3-(difluoromethyl)-2-methylphenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine -6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[4-({(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyri midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[2-methyl-4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidine-6- 1]-1,4lambda ⁵ amino-azaphosphinan-4-one
(R)-1-(4-(4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)- 2-methylpyrido[3,4-d]pyrimidin-6-yl)-4-oxido-1,4-azaphosphinan-1-yl)ethan-1-one
1-Acetyl-4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-2-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-Acetyl-4-[2-(difluoromethyl)-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ azaphosphinan-4-one
1-Acetyl-4-[2-chloro-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrido midin-6-yl]-1,4lambda ⁵ amino-azaphosphinan-4-one
1-acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazolin-6-yl]-1, 4lambda ⁵ -azaphosphinan-4-one
N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)methanesulfonamide
N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)acetamide
N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylmethanesulfonamide
N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-methylacetamide
N-(2-{3-[(1R)-1-{[6-(1-acetyl-4-oxo-1,4lambda ⁵ -azaphosphinan-4-yl)-2-methylpyrido[3 ,4-d]pyrimidin-4-yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethyl)-N-cyclopropylacetamide
1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3, 4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
4-[4-({(1R)-1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)-2-methylpyrido[3,4-d]pyrimidine-6- Il]-1-(difluoroacetyl)-1,4lambda ⁵ amino-azaphosphinan-4-one
1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d] pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-(difluoroacetyl)-4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[3 ,4-d]pyrimidin-6-yl]-1,4lambda ⁵ -azaphosphinan-4-one
1-(difluoroacetyl)-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)quinazoline-6- 1]-1,4lambda ⁵ -azaphosphinan-4-one
or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. 17. A compound of formula (I) according to any one of claims 1 to 16 for use in the treatment or prevention of disease. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 and one or more pharmaceutically acceptable excipients. Pharmaceutical combination comprising:
· at least one first active ingredient, in particular a compound of formula (I) according to any one of claims 1 to 16, and
· One or more additional active ingredients, in particular: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, Patinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin , amsacrine, anastrozole, ancestim, anethole dithiolethion, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arsitumomab, arglavine, arsenic trioxide, Asparaginase, atezolizumab, avelumab, axicaptagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, becilesomab, belinostat, bevacizumab, beck Sarothene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonin , calcium folinate, calcium levofolate, capecitabine, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, selmo Leukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormetin, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, Copanlisib, chrysantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, darolutamide, Satinib, daunorubicin, decitabine, degarelix, denileukin diptitox, denosumab, defreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol , diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, Eltrombopag, enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, Esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, Fluda Labine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, meglumine gadoterate, gadoversetamide, Gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride. , histrelin, hydroxycarbamide, I-125 seed, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan. , indicetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alpha, interferon beta, interferon gamma, iobitridol, iobenguan (123I), iomeprol, ipilimumab, Irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levo Norgestrel, Levothyroxine Sodium, Lisuride, Lobaplatin, Lomustine, Ronidamine, Lutetium Lu 177 Dotatate, Masoprocol, Medroxyprogesterone, Megestrol, Melarsoprol, Melphalan, Mephithiostane , mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metyrosine, midostaurin, mifamurtide, miltefosine, myriplatin, mitobronitol, mitogua. John, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, furidamole, morphine hydrochloride, morphine sulfate, embassy, nabilone, nabiximols, nafarelin, naloxone + Pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, neil Lutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxin mephesuccinate , omeprazole, ondansetron, ofrelbechin, orgoteine, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103. Seeds, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, Pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peflomycin, perflubutan, perphosphamide, pertuzumab, picivanil, pilocarpine, pirarubi. Cin, pixantrone, plerixapor, plicamycin, polyglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, Pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron. , ramucirumab, ranimustine, rasburcase, razoxan, lepametinib, regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin , romiplostim, romurtide, rucaparib, samarium (153Sm), lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizopiran, sobuzoxan, Sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporphin, talimogen laherparepvec, tamibalotene, tamoxifen, tapentadol, tasonermine, tesleukin. , technetium (99mTc) nofetumomab merpentane, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporphine, temozolomide, temsirolimus , teniposide, testosterone, tetrophosmine, thalidomide, thiotepa, thymalfacin, thyrotropin alfa, thioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumo Mab, Trabectedin, Trametinib, Tramadol, Trastuzumab, Trastuzumab Emtansine, Treosulfan, Tretinoin, Trifluridine + Tipiracil, Trilostane, Triptorelin, Trametinib, Trophosphamide, Throm Bopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, barley Norstat, vorozole, yttrium-90 glass microspheres, genostatin, ginostatin stimalamer, zoledronic acid, zorubicin. Use of a compound of formula (I) according to any one of claims 1 to 16 for the treatment or prevention of diseases. Use of a compound of formula (I) according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment or prevention of diseases. Use according to any one of claims 17, 20 and 21, wherein the disease is hyperproliferative nomenclature disorder, such as for example certain disorders. Humans and animals by administering an antihyperproliferative effective amount of at least one compound as defined in any one of claims 1 to 16 or a medicament as defined in any of claims 17 to 21. How to control...